Autosomal Dominant Nonsyndromic Hearing Loss 25

Mendelian MONDO:0011568 Pathograph 13 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss Hereditary Hearing Loss

Delayed-onset, progressive, predominantly high-frequency sensorineural hearing loss caused by heterozygous variants in SLC17A8, which encodes vesicular glutamate transporter 3 (VGLUT3). VGLUT3 is the transporter that fills the synaptic vesicles of the cochlear inner hair cell with glutamate before they are released onto the auditory nerve terminal, so the gene sits at the very first synapse of hearing. Among the three vesicular glutamate transporters it is the only one expressed in inner hair cells, which is why a defect in it produces deafness and almost nothing else. Two things make this entry worth reading rather than filing as one more DFNA locus. The first is that the gene's function makes DFNA25 look like an auditory synaptopathy and the patients do not behave like one. The Slc17a8 null mouse is a textbook synaptopathy: otoacoustic emissions are robust, sound-evoked auditory-nerve responses are absent, and brainstem responses can still be driven electrically, so the cochlear amplifier is intact and the step after it is not. The knock-in mouse carrying the actual human allele has intact emissions too. But in the patients carrying that same allele, otoacoustic emissions are absent - the opposite result - and the knock-in study concludes on that basis that DFNA25 is more likely a progressive hearing loss than an auditory neuropathy. Whether those absent emissions are the disease or a lifetime of accumulated noise exposure is unresolved, and it is the question that decides which class this disease belongs to. The second is that the two mouse models disagree about where the lesion starts. The null points at vesicle filling. The knock-in points at the hair bundle: inner hair cell stereocilia collapse while outer hair cell bundles do not, the summating potential falls, and the synaptic changes - oversized ribbons, a faster sustained release rate - appear later. That is mechanistically surprising, because VGLUT3 is not present in inner hair cell stereocilia and its loss does not affect transducer activity, so no route from the transporter to the bundle is established. This entry curates both accounts as hypothesis groups rather than choosing between them. The third is that neither mouse has the genotype a patient has. Both are homozygous. The heterozygous knock-in - the genotype that matches a DFNA25 carrier - has only mild hearing impairment, which its authors note contrasts with the dominant transmission seen in the human families. Because truncating and splice alleles have since been reported in dominant families too, the allelic mechanism has to be argued case by case rather than assumed from the gene. Clinically the disease is easy to miss. It is postlingual, slowly progressive and high-frequency, which is the audiometric shape of presbycusis and of noise damage, and the founding clinical study says in as many words that separating it from those is difficult. Penetrance is age-dependent and, in the original kindred, appeared to depend on which parent transmitted the haplotype.

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Inheritance
8
Pathophys.
5
Phenotypes
2
Hypotheses
4
Gaps
13
Pathograph
1
Genes
3
Medical Actions
3
Differentials
2
Models
13
References
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Every reported proband is heterozygous and the trait segregates vertically through multiple generations. Penetrance is age-dependent, so an unaffected young carrier does not exclude the diagnosis and phenotype-based testing of relatives is unreliable.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:12925340 SUPPORT Human Clinical
"The mode of inheritance is autosomal dominant with age-dependent penetrance."
Inheritance mode and the penetrance qualifier together.
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Mechanistic Hypotheses

2
Presynaptic vesicular glutamate loading failure
presynaptic_glutamate_loading_failure CANONICAL
The account that follows from what VGLUT3 does. Without the transporter the inner hair cell still fuses vesicles on schedule, but the vesicles are empty, so the auditory nerve is never driven while the outer hair cells keep amplifying. This is what the Slc17a8 null mouse shows and it is the reason DFNA25 is discussed alongside the auditory synaptopathies. It has two limitations. The null mouse is homozygous and congenitally deaf, whereas DFNA25 patients are heterozygous and lose hearing slowly in adult life. And the audiological prediction it makes - preserved otoacoustic emissions - is contradicted in the patients, whose emissions are absent. It is kept as the canonical group because it is what the transporter does and what the null animal shows, not because the human audiology supports it.
Pathograph links
Altered VGLUT3 Function in the Inner Hair Cell -> Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse DIRECT The direct consequence of an unfilled vesicle, and the route the null mouse takes.
Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse -> Failure of Auditory Nerve Activation with Preserved Cochlear Amplification DIRECT An afferent terminal that receives no transmitter does not fire, however well the cochlea in front of it is working.
Stereociliary mechanotransduction failure preceding synaptic change
a211v_mechanotransduction_first EMERGING
The account that follows from the mouse carrying the human allele rather than a deletion. In the VGLUT3 A224V knock-in the inner hair cell hair bundles collapse and the summating potential - the receptor potential of the inner hair cell - falls, while cochlear amplification stays intact; the ribbon changes come afterwards. On this reading the primary lesion in DFNA25 is the transduction apparatus and the synapse is a downstream casualty, which would place the disease outside the synaptopathies rather than inside them. It is one model, homozygous for an allele patients carry heterozygously, so this is recorded as emerging rather than established.
Pathograph links
Altered VGLUT3 Function in the Inner Hair Cell -> Inner Hair Cell Stereocilia Bundle Disruption INDIRECT UNKNOWN INTERMEDIATES The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no mechanism connecting an altered vesicular transporter to hair-bundle architecture has been demonstrated; the knock-in shows the bundles collapse, not why.
Inner Hair Cell Stereocilia Bundle Disruption -> Reduced Inner Hair Cell Receptor Potential DIRECT A collapsed bundle is a bundle that transduces less, and the summating potential falls in the same animals.
Reduced Inner Hair Cell Receptor Potential -> Synaptic Ribbon Enlargement and Altered Sustained Exocytosis INDIRECT UNKNOWN INTERMEDIATES The knock-in paper orders these two findings in time - transduction first, synaptic change later - so the edge records a sequence the model establishes rather than a demonstrated causal step.
Reduced Inner Hair Cell Receptor Potential -> Failure of Auditory Nerve Activation with Preserved Cochlear Amplification DIRECT A receptor potential that does not reach normal amplitude drives less transmitter release, whatever state the vesicles are in.
Synaptic Ribbon Enlargement and Altered Sustained Exocytosis -> Failure of Auditory Nerve Activation with Preserved Cochlear Amplification INDIRECT UNKNOWN INTERMEDIATES Altered rather than absent transfer, in an animal whose brainstem responses are progressively lost. The link is INDIRECT because the paper does not show that the ribbon change is what degrades the response.
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Discussions and Knowledge Gaps

4
Does either mouse model DFNA25, when both are homozygous and the heterozygote - the genotype a patient actually has - is only mildly affected?
HUMAN MODEL MISMATCH OPEN mismatch_zygosity_of_the_dfna25_mouse_models
Attached to
pathophysiology#Heterozygous SLC17A8 Variant animal_models#Mouse
This is not a fidelity quibble; it is a mismatch about the genetic mechanism itself. Both published models are homozygous: the Slc17a8 null, which is congenitally and profoundly deaf, and the A224V knock-in, which is progressively deaf. The heterozygous knock-in has been phenotyped, and it is the genotype that corresponds to a DFNA25 carrier. It shows a small threshold shift that reaches statistical significance but leaves brainstem response amplitudes indistinguishable from wild-type littermates - which the authors themselves say contrasts with the dominant transmission seen in the human families. Their explanation is that the stereocilia change is slow relative to a mouse lifespan, so a mouse simply does not live long enough to reach the human phenotype from one allele. That is plausible and untested. The alternative is that the human allele does something in a human inner hair cell that it does not do in a mouse one, in which case the homozygous findings are a dose artefact. The stake is therapeutic. AAV gene addition rescues the null mouse, and gene addition is the obvious translation. But it is the right strategy only if the human allele acts by loss of function. If p.A211V is a dominant negative or a toxic gain of function, adding wild-type VGLUT3 to a cell that already has a working copy may not help, and an allele-selective knockdown would be the rational target instead. Nothing published distinguishes those, which is also why the trigger node leaves `functional_impact_category` empty. The authors' own summary is that the knock-in "might be arguable so far as to consider it as a faithful model of DFNA25".
Proposed experiments
Lifespan-long auditory phenotyping of heterozygous VGLUT3 A224V mice
dfna25_aged_heterozygous_knockin
Follow VGLUT3+/A224V mice to the end of their natural lifespan with serial brainstem responses, distortion-product emissions and inner hair cell bundle morphology, rather than stopping at six months. If the published mild phenotype is a matter of mouse lifespan, the deficit should continue to widen against age-matched wild-type littermates; if it plateaus, one allele is not sufficient in a mouse.
Would support
pathophysiology#Heterozygous SLC17A8 Variant
Supporting outcome
  • The heterozygous deficit keeps widening with age and the bundles progressively distort, which would make the mouse an under-aged version of the human disease rather than a different one, and would license reading the homozygous mechanism across to patients.
Refuting outcome
  • The heterozygous deficit plateaus and the bundles stabilise, which would mean one copy of the variant allele is tolerated in a mouse and is not in a human - leaving the dominant mechanism of DFNA25 unmodelled by either animal.
Are otoacoustic emissions absent in DFNA25 patients because of the disease, or because of a lifetime of noise exposure?
KNOWLEDGE GAP OPEN gap_why_patient_emissions_are_absent
Attached to
phenotypes#Absent Otoacoustic Emissions mechanistic_hypotheses#presynaptic_glutamate_loading_failure
This is the question that decides what class DFNA25 belongs to, and it is not a technicality about a test. Every model says emissions should be preserved. The Slc17a8 null has robust emissions, the A224V knock-in has decent distortion-product emissions, and VGLUT3-null data are taken as evidence that VGLUT3 has no role in cochlear amplification at all. In the patients, emissions are absent. If that is the disease, then outer hair cell function is involved, DFNA25 is not an auditory synaptopathy, and the knock-in study's conclusion - that this is a progressive hearing loss rather than an auditory neuropathy - stands. But DFNA25 is a postlingual disease of adults with a high-frequency audiogram, which is exactly the population and exactly the audiometric shape in which acquired noise damage is hardest to exclude. The same authors raise noise as the alternative explanation and do not test it. If noise is the answer, the underlying disease could still be a synaptopathy whose audiological signature has been erased by an acquired overlay - and the entry would be filing it in the wrong class on the strength of a confounded measurement. Nothing about DFNA25 makes noise exposure implausible; the disease is diagnostically confusable with noise-induced hearing loss in the first place, which is recorded as its main differential. The authors propose the discriminating experiment themselves.
Proposed experiments
Noise vulnerability in mice carrying one or two VGLUT3-p.A224V alleles
dfna25_noise_vulnerability_by_allele_dose
Expose wild-type, heterozygous and homozygous A224V mice to a controlled acoustic overexposure and compare distortion-product emission loss and threshold shift against unexposed littermates. This is the experiment the knock-in authors name as necessary to determine whether acoustic injury accounts for the discrepancy between mouse and patient emissions.
Would support
phenotypes#Absent Otoacoustic Emissions
Supporting outcome
  • Variant-carrying mice lose emissions disproportionately after noise, which would mean the absent emissions in patients are an acquired overlay on a genetic synaptopathy, would keep DFNA25 inside the auditory neuropathy spectrum, and would make hearing protection a disease-modifying intervention rather than general advice.
Refuting outcome
  • Variant-carrying mice are no more noise-vulnerable than wild type, which would leave the absent patient emissions as a feature of the disease itself, confirm that outer hair cell function is involved, and settle DFNA25 outside the synaptopathies.
How does a vesicular glutamate transporter variant collapse the inner hair cell stereocilia bundle?
KNOWLEDGE GAP OPEN gap_where_the_dfna25_lesion_starts
Attached to
mechanistic_hypotheses#presynaptic_glutamate_loading_failure mechanistic_hypotheses#a211v_mechanotransduction_first
The knock-in mouse's primary finding is that inner hair cell bundles fuse and collapse while outer hair cell bundles are spared, and no proposed mechanism survives contact with what is already known about the protein. VGLUT3 is not present in inner hair cell stereocilia. Losing VGLUT3 entirely leaves the transducer working, with an intact hair cell receptor potential. So the variant is doing something the null does not. The paper's own candidate is a misfolding-and-aggregation model, in which variant protein accumulates near the nucleus and jams the traffic that maintains the stereocilia machinery - borrowing the mechanism established for DIAPH3 in the auditory neuropathy AUNA1. It then argues against its own candidate on two counts: the same point mutation reduces VGLUT3 in nerve terminals while leaving the soma unchanged, which is the opposite of somatic accumulation, and a structural model shows alanine-to-valine barely perturbs the protein. This matters beyond tidiness. The two hypothesis groups in this entry diverge at exactly this step, and a gene therapy designed against the synaptic account would not address a stereociliary lesion.
Proposed experiments
Subcellular localisation and turnover of VGLUT3-p.A224V in inner hair cells
dfna25_vglut3_localisation_in_knockin_hair_cells
Track variant VGLUT3 in knock-in inner hair cells by immunogold electron microscopy and pulse-chase, testing directly whether it accumulates in the soma or apical compartment, whether proteostasis markers are engaged, and whether the cuticular plate cytoskeleton is disturbed before the bundles collapse.
Would support
mechanistic_hypotheses#a211v_mechanotransduction_first
Supporting outcome
  • Variant protein accumulates with an engaged proteostasis response and cuticular-plate disturbance preceding bundle collapse, which would supply the missing mechanism and establish the transduction account as the primary one.
Refuting outcome
  • Variant protein localises normally and no proteostasis or cytoskeletal change precedes the bundle collapse, which would leave the stereocilia phenotype unexplained and raise the possibility that it is a strain or background effect of this particular mouse line rather than a consequence of the allele.
Do the truncating and splice SLC17A8 alleles cause the same disease as the missense founder allele?
KNOWLEDGE GAP OPEN gap_dfna25_allele_class_heterogeneity
Attached to
genetic#SLC17A8
The entry treats SLC17A8 as one causative gene because that is how the gene-disease relationship is curated, but the alleles do not obviously share a mechanism. p.A211V is a conserved missense that leaves vesicular glutamate accumulation intact where it has been tested. p.M206Nfs*4 truncates at residue 209 and removes most of the transmembrane domains. c.763+1G>T abolishes a splice donor. In vitro work on two further suspected alleles found one reduced transcript and protein while the other left transcript alone and produced an abnormal protein. If the truncating alleles are simple loss of function, then a heterozygous truncating carrier is functionally a heterozygous null - and heterozygous null mice hear normally. Either mice and humans differ in their tolerance of half-dose VGLUT3, or the truncating alleles are doing something other than reducing dosage, or their pathogenicity rests on smaller families than the founder allele's. Each of those has a different consequence for variant interpretation in a diagnostic laboratory.
Proposed experiments
Audiometric comparison of missense against truncating SLC17A8 carriers
dfna25_allele_class_audiogram_comparison
Collect audiograms and ages at onset across all published SLC17A8 heterozygotes and compare the founder missense families against the frameshift and splice-donor families, testing whether onset, progression rate and audiometric shape differ by allele class.
Would support
genetic#SLC17A8
Supporting outcome
  • The allele classes are audiometrically indistinguishable, supporting a single gene-level disease entity and justifying the current single causative-gene record.
Refuting outcome
  • Truncating carriers are milder, later or less penetrant than missense carriers, which would mean DFNA25 as curated conflates two mechanisms and that a truncating SLC17A8 variant should not be reported with the same prognosis as the founder allele.
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Pathophysiology

8
Heterozygous SLC17A8 Variant
The founding and best-characterised allele is the missense c.632C>T, p.A211V, which segregated with deafness in two apparently unrelated families sharing a distant common ancestor and was absent from 267 controls. The alanine is conserved across species and across all three human VGLUT paralogues. Later reported dominant alleles are of a different kind: a frameshift, p.M206Nfs*4, predicted to truncate the protein at residue 209 and remove transmembrane domains 5 to 12, and a canonical splice-donor variant, c.763+1G>T. Whether these act by the same route as the missense allele is not established, and the entry does not assume it.
Genetic context SLC17A8 hgnc:20151 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SLC17A8 (hgnc:20151). hgnc:20151 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS
Heterozygous in every reported family. `functional_impact_category` is deliberately left empty: heterozygous Slc17a8 knockout mice hear normally while heterozygous human p.A211V carriers do not, so the missense allele is not behaving as a simple loss-of-function, and no dominant-negative or gain-of-function experiment has been done to license one of the narrower values instead. The truncating and splice alleles may well be loss-of-function, but they sit in the same slot on the same node and the category is single-valued.
Downstream
Altered VGLUT3 Function in the Inner Hair Cell Every proposed mechanism for this disease runs through the transporter that the variant sits in.
Show evidence (4 references)
PMID:18674745 SUPPORT Human Clinical
"In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls."
The founding allele, its zygosity, its segregation and its control screening.
PMID:18674745 SUPPORT Human Clinical
"The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role."
The conservation argument the founding paper rests the missense call on.
PMID:26797701 SUPPORT Human Clinical
"The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to asparagine at amino acid position 206, resulted in a termination codon at amino acid position 209."
A truncating dominant allele, structurally quite unlike the founding missense.
+ 1 more reference
Altered VGLUT3 Function in the Inner Hair Cell
VGLUT3 is the vesicular glutamate transporter of the cochlear inner hair cell: it accumulates glutamate inside the synaptic vesicle so that the vesicle has something to release when it fuses. Of the three VGLUT paralogues it is the only one selectively expressed in inner hair cells, which is why the cochlear phenotype is not compensated by VGLUT1 or VGLUT2 and why an otherwise widely expressed transporter gives a nonsyndromic deafness. What the human p.A211V substitution does to that function is the open part. It does not impair vesicular glutamate accumulation, quantal release or quantal content when tested in hippocampal autaptic neurons, and in the knock-in mouse it lowers VGLUT3 protein in central terminals by roughly seventy per cent without changing VGLUT3-dependent behaviour. So the allele is not a straightforward transport-dead mutant, and the two hypothesis groups below diverge from this node rather than from the variant.
Presynaptic vesicular glutamate loading failure Stereociliary mechanotransduction failure preceding synaptic change
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
glutamate loading into inner hair cell synaptic vesicles GO:0098700 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutamate loading into inner hair cell synaptic vesicles, annotated with neurotransmitter loading into synaptic vesicle (GO:0098700). GO:0098700 is a biological process from the Gene Ontology. ↓ DECREASED
vesicular L-glutamate transport by VGLUT3 GO:0005313 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased vesicular L-glutamate transport by VGLUT3, annotated with L-glutamate transmembrane transporter activity (GO:0005313). GO:0005313 is a molecular function from the Gene Ontology. ↓ DECREASED
inner hair cell synaptic vesicle GO:0008021 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves inner hair cell synaptic vesicle, annotated with synaptic vesicle (GO:0008021). GO:0008021 is a cellular component from the Gene Ontology.
Downstream
Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse The direct consequence of an unfilled vesicle, and the route the null mouse takes. Presynaptic vesicular glutamate loading failure
Inner Hair Cell Stereocilia Bundle Disruption The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no mechanism connecting an altered vesicular transporter to hair-bundle architecture has been demonstrated; the knock-in shows the bundles collapse, not why. Stereociliary mechanotransduction failure preceding synaptic change
Show evidence (3 references)
PMID:18674745 SUPPORT Model Organism
"In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals."
The normal function of the protein, which is what the disease removes or alters.
PMID:26797701 SUPPORT Other
"among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair cells (IHCs)"
Why there is no paralogue to compensate in the inner hair cell, and therefore why the phenotype is cochlear and nonsyndromic.
PMID:34783032 SUPPORT In Vitro
"This variation does not impair the glutamate vesicular accumulation, neither the quantal release nor the quantal content in hippocampal autaptic neurons"
A negative result at the level of transport itself, which is why this entry does not assert that the human missense allele simply stops glutamate loading. Graded IN_VITRO because the measurement is in cultured autaptic neurons.
Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
In the Slc17a8 null cochlea the machinery of release is intact and the cargo is not. Calcium-triggered vesicle turnover measured by membrane capacitance is normal at two weeks of age, and the ribbon synapses that survive to three months look normal under the electron microscope. What is missing is the glutamate, so the vesicles fuse and the afferent terminal is not driven.
Presynaptic vesicular glutamate loading failure
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
glutamate secretion at the inner hair cell afferent synapse GO:0014047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutamate secretion at the inner hair cell afferent synapse, annotated with glutamate secretion (GO:0014047). GO:0014047 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Slc17a8 null mouse Mouse recapitulates The release failure and its localisation to vesicle content rather than fusion, both measured directly in the correct cell type.
Downstream
Failure of Auditory Nerve Activation with Preserved Cochlear Amplification An afferent terminal that receives no transmitter does not fire, however well the cochlea in front of it is working. Presynaptic vesicular glutamate loading failure
Show evidence (3 references)
PMID:18215623 SUPPORT Model Organism
"We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway."
The release failure stated directly, and its location at the first auditory synapse.
PMID:18674745 SUPPORT Model Organism
"Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age."
The deliberate negative result that localises the defect to vesicle content rather than to exocytosis. Without it the node would be indistinguishable from a fusion defect.
PMID:18674745 SUPPORT Model Organism
"We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse."
The founding paper's own conclusion about the null animal.
Inner Hair Cell Stereocilia Bundle Disruption
In the knock-in mouse carrying the human allele, scanning electron microscopy shows the inner hair cell stereocilia bundles collapsing and fusing while the outer hair cell bundles are left alone. That selectivity matters: it is the same cell-type restriction as the transporter's expression, and it means the finding is not general hair-cell degeneration. No mechanism links a vesicular glutamate transporter to hair-bundle architecture, and the finding is surprising on its own terms: VGLUT3 is not present in inner hair cell stereocilia, and losing VGLUT3 altogether leaves the transducer working, with an intact hair cell receptor potential. The paper's own candidate explanation - that the variant protein misfolds and aggregates, disrupting traffic towards the stereocilia machinery - is argued against by two earlier results it cites: the point mutation reduces VGLUT3 in nerve terminals while leaving the soma unchanged, and a structural model shows that swapping alanine for valine barely changes the protein. The node is curated because the allele-matched model reports it as the primary lesion, not because the connection is understood.
Stereociliary mechanotransduction failure preceding synaptic change
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
inner hair cell stereocilium bundle organization GO:0060122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inner hair cell stereocilium bundle organization, annotated with inner ear receptor cell stereocilium organization (GO:0060122). GO:0060122 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
VGLUT3 A224V knock-in mouse Mouse recapitulates Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell bundles spared - the model's primary structural finding.
Downstream
Reduced Inner Hair Cell Receptor Potential A collapsed bundle is a bundle that transduces less, and the summating potential falls in the same animals. Stereociliary mechanotransduction failure preceding synaptic change
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected."
The bundle finding and its restriction to inner hair cells.
Reduced Inner Hair Cell Receptor Potential
The summating potential is the gross cochlear correlate of the inner hair cell receptor potential, and it is reduced in the knock-in mouse. Because cochlear amplification is intact in the same animals, a smaller receptor potential is being generated from a normal mechanical input - which is what a transduction defect in the inner hair cell looks like from outside.
Stereociliary mechanotransduction failure preceding synaptic change
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
mechanotransduction in the inner hair cell hair bundle GO:0050910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mechanotransduction in the inner hair cell hair bundle, annotated with detection of mechanical stimulus involved in sensory perception of sound (GO:0050910). GO:0050910 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
VGLUT3 A224V knock-in mouse Mouse recapitulates The functional counterpart of the bundle collapse, measured as a reduced summating potential in an animal whose cochlear amplifier is intact.
Downstream
Synaptic Ribbon Enlargement and Altered Sustained Exocytosis The knock-in paper orders these two findings in time - transduction first, synaptic change later - so the edge records a sequence the model establishes rather than a demonstrated causal step. Stereociliary mechanotransduction failure preceding synaptic change
Failure of Auditory Nerve Activation with Preserved Cochlear Amplification A receptor potential that does not reach normal amplitude drives less transmitter release, whatever state the vesicles are in. Stereociliary mechanotransduction failure preceding synaptic change
Show evidence (2 references)
PMID:34783032 SUPPORT Model Organism
"The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential."
The measurement and the authors' own interpretation of it.
PMID:34783032 SUPPORT Model Organism
"These results suggest that DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer."
The ordering claim that this hypothesis group is built on, stated by the authors as a suggestion rather than a demonstration - which is why the group is EMERGING.
Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
Later in the knock-in mouse the ribbons grow oversized and the rate of sustained releasable pool exocytosis rises. This is a change in synaptic transfer rather than a loss of it, and it points the same way as the null mouse's ribbon morphology, where ribbons are described as abnormally thin and elongated. Whether an enlarged ribbon with a faster sustained release rate is compensatory or maladaptive has not been tested.
Stereociliary mechanotransduction failure preceding synaptic change
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
sustained glutamate release from the inner hair cell ribbon synapse GO:0014047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sustained glutamate release from the inner hair cell ribbon synapse, annotated with glutamate secretion (GO:0014047). GO:0014047 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
VGLUT3 A224V knock-in mouse Mouse recapitulates Oversized ribbons and a faster sustained release rate, appearing later than the transduction findings.
Downstream
Failure of Auditory Nerve Activation with Preserved Cochlear Amplification Altered rather than absent transfer, in an animal whose brainstem responses are progressively lost. The link is INDIRECT because the paper does not show that the ribbon change is what degrades the response. Stereociliary mechanotransduction failure preceding synaptic change
Show evidence (2 references)
PMID:34783032 SUPPORT Model Organism
"Using super-resolution microscopy, we observed oversized synaptic ribbons and patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis."
Both halves of this node, measured directly.
PMID:34783032 SUPPORT Model Organism
"In addition, IHC ribbon synapses underwent structural and functional modifications at later stages."
The timing, which is what makes this node downstream of the transduction node rather than parallel to it.
Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
The convergence point of both hypothesis groups, and the finding that puts DFNA25 in the same conversation as the auditory synaptopathies - in the models, at least. In the null mouse, sound-evoked auditory-nerve responses are absent while otoacoustic emissions are robust, and brainstem responses can still be evoked electrically - so the cochlear amplifier and the ascending pathway both work and the step between them does not. In the knock-in mouse the same dissociation appears in progressive form: brainstem responses deteriorate with age while distortion-product emissions stay intact. This is a mouse finding, and in the patients it does not hold. Otoacoustic emissions are reported absent in carriers of the p.A211V allele - the opposite of both mice - which is why the knock-in study concludes that DFNA25 in humans is more likely a progressive hearing loss than an auditory neuropathy. The node is therefore curated as what the models show, not as a human phenotype, and the absent-emissions finding is curated separately under phenotypes.
type 1 spiral ganglion neuron CL:4023115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type 1 spiral ganglion neuron (CL:4023115). CL:4023115 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
organ of Corti UBERON:0002227 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in organ of Corti, annotated with spiral organ of cochlea (UBERON:0002227). UBERON:0002227 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Slc17a8 null mouse Mouse recapitulates The three-way dissociation - no acoustic neural response, intact emissions, intact electrically evoked brainstem response - measured in one animal.
Downstream
Secondary Deafferentation of the Inner Hair Cell An afferent synapse that is never driven does not survive indefinitely, and in the null mouse the synapses, the neurons and the efferent endings all decline later.
Progressive High-Frequency Sensorineural Hearing Loss The clinical phenotype is what an auditory nerve that is inadequately driven produces.
Show evidence (3 references)
PMID:18674745 SUPPORT Model Organism
"Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded."
All three halves of the dissociation in one sentence: no acoustic neural response, preserved electrical response, preserved emissions.
PMID:34783032 SUPPORT Model Organism
"Using auditory brainstem response and distortion product otoacoustic emissions, we showed progressive hearing loss with intact cochlear amplification in the VGLUT3A224V/A224V mouse."
The same dissociation in the allele-matched model, and in progressive rather than congenital form.
PMID:34783032 REFUTE Human Clinical
"Decent DPOAEs were recorded in the knock-in mutant mouse. In contrast, otoacoustic emissions were absent in patients harbouring the p.A211V allele"
Refutes this node as a human phenotype. The preserved-amplification half of the dissociation is a mouse result that the patients contradict, which is the single most important qualification on this entry. Graded HUMAN_CLINICAL because the quoted clause reports a patient audiological finding, even though the paper is otherwise a mouse study.
Secondary Deafferentation of the Inner Hair Cell
In the null mouse the afferent synapses beneath the inner hair cells, the spiral ganglion neurons themselves and the lateral efferent endings all decline with time, and some cochlear ganglion neurons degenerate early enough that the glutamate released before hearing onset is inferred to have a developmental role rather than only a signalling one. Aged null cochleae show degeneration of inner hair cells, synapses and stereocilia together. This matters clinically because it is the part of the disease a therapy would have to outrun.
spiral ganglion neuron CL:0011113 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spiral ganglion neuron (CL:0011113). CL:0011113 is a cell type from the Cell Ontology.
Animal models
Slc17a8 null mouse Mouse recapitulates The afferent synapses, spiral ganglion neurons and lateral efferent endings decline after the functional deficit is established.
Downstream
Progressive High-Frequency Sensorineural Hearing Loss Loss of the afferent population adds an irreversible component to a deficit that began as a functional one.
Show evidence (3 references)
PMID:18674745 SUPPORT Model Organism
"Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined."
The deafferentation itself, and its late timing relative to the functional deficit.
PMID:18215623 SUPPORT Model Organism
"The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing."
The developmental component, which is a different claim from use-dependent loss and is the reason a congenital null and an adult-onset human disease may diverge here.
PMID:40841774 SUPPORT Model Organism
"In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia."
The structural endpoint in the aged null animal.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Nonsyndromic Hearing Loss 25 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Ear 3
Progressive High-Frequency Sensorineural Hearing Loss High-frequency sensorineural hearing impairment HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757), qualified as course progressive. HP:0001757 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:11115382 SUPPORT Human Clinical
"we identified a novel dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational United States family of Czech descent."
The phenotype as defined at the locus, in the founding kindred.
PMID:18674745 SUPPORT Human Clinical
"We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness."
The same phenotype restated once the gene was in hand.
Postlingual Delayed Onset Postlingual sensorineural hearing impairment HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12925340 SUPPORT Human Clinical
"Affected individuals typically manifest a high-frequency, slowly progressive sensorineural hearing loss in the postlingual period."
Onset timing, from the serial-audiogram study of the founding family.
Absent Otoacoustic Emissions HP:6000182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent otoacoustic emissions (HP:6000182). HP:6000182 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34783032 SUPPORT Human Clinical
"In contrast, otoacoustic emissions were absent in patients harbouring the p.A211V allele"
The human audiological finding itself. Graded HUMAN_CLINICAL because the clause reports a patient measurement, although the paper it appears in is a mouse study.
PMID:34783032 SUPPORT Human Clinical
"Thus, DFNA25 is more likely to be a progressive hearing loss in human rather than an auditory neuropathy"
The classification conclusion the authors draw from it, which is the reason this entry does not file DFNA25 under the auditory neuropathy spectrum.
PMID:34783032 NO_EVIDENCE Human Clinical
"The lack of otoacoustic emissions in DFNA25 patients might be due to additional factors encountered during lifetime such as noise"
The competing explanation, offered by the same authors as a possibility they did not test. Graded NO_EVIDENCE because it reports a hypothesis rather than a result, and it is the reason the classification above is recorded as a conclusion rather than as settled.
Other 2
Age-Dependent Penetrance
Show evidence (3 references)
PMID:12925340 SUPPORT Human Clinical
"The mode of inheritance is autosomal dominant with age-dependent penetrance."
The penetrance statement itself.
PMID:12925340 SUPPORT Human Clinical
"In those inheriting the DFNA25-associated haplotype from an affected mother, hearing loss invariably developed by the second decade of life, whereas those inheriting the DFNA25 haplotype from an affected father often maintained hearing levels comparable to those of age-matched control subjects,..."
The parent-of-origin observation, quoted in full so the size and source of the claim travel with it.
PMID:12925340 SUPPORT Human Clinical
"None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G, Cins7472, and 7511T>C) were found to segregate in the family."
Records that the obvious maternal-transmission explanation was tested and excluded in this family.
Absence of Syndromic Features
Show evidence (3 references)
PMID:28647561 SUPPORT Human Clinical
"the clinical information about this family revealed that there are no other symptoms accompanied with HL"
The nonsyndromic statement in a reported dominant family.
PMID:41279968 SUPPORT Model Organism
"In behavioral studies, Vglut3 -/- mice did not exhibit considerable sensorimotor or balance deficits."
Vestibular sparing in the model, which is why the human phenotype being purely cochlear is expected rather than surprising.
PMID:41279968 SUPPORT Model Organism
"Collectively, these data support the view that non-quantal transmission is the predominant mode of neurotransmission between type I VHCs and vestibular calyceal afferent neurons."
The mechanism of the sparing - a parallel transmission mode that the cochlear afferent synapse does not have.
🧬

Genetic Associations

1
SLC17A8
Gene: SLC17A8 hgnc:20151 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC17A8 (hgnc:20151). hgnc:20151 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other
"Variants in this gene segregated with disease in 28 additional members in two families"
The segregation evidence behind the Definitive classification.
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other
"In summary, SCL17A8 is definitively associated with autosomal dominant nonsyndromic hearing loss."
The panel's summary sentence. The gene symbol is transposed in the source record and is quoted as written.
🗃️

External Assertions

1
ClinGen SLC17A8-nonsyndromic hearing loss gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal dominant SLC17A8-nonsyndromic hearing loss relationship as Definitive. The classification was raised from Strong in 2018 to Definitive in 2023 on additional case-level evidence, and the panel's own count of the evidence base - nine probands, eight variants, twenty-eight additional segregating relatives - is the best available statement of how small this disease's human literature is.
Show evidence (3 references)
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other
"SLC17A8 | HGNC:20151 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Definitive"
The expert-panel classification row itself, with gene, disease, inheritance mode and verdict.
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other
"At least 8 unique variants (missense, frameshift, splice site) have been reported in humans in 9 probands"
The size of the human evidence base, which is the number every frequency and prevalence statement in this entry has to be read against.
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other
"As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence"
Records that the Definitive verdict is recent and was reached by upgrade, not asserted at first curation.
💊

Medical Actions

3
Hearing Aids
Action: hearing aid fittingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid fitting, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Amplification is the first-line management of a progressive high-frequency sensorineural loss and is what DFNA25 patients receive in practice. No DFNA25-specific outcome has been published. Whether it should be expected to work well depends on which class this disease turns out to be in, which is unresolved. If the null mouse's synaptopathy account holds in humans there is a mechanistic reason to expect amplification to underperform its audiometric gain, since amplification addresses sensitivity and a failure of neural encoding is not a sensitivity problem. If instead the absent patient emissions mean outer hair cell function is involved, amplification is addressing the right deficit. Nothing here is asserted either way; the question is carried by the emissions knowledge gap.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Biologically plausible in this disease for a specific reason rather than a general one: in the null mouse the ascending auditory pathway can still be driven by electrical stimulation even though it cannot be driven by sound, so an implant that bypasses the inner hair cell synapse has an intact target. Whether that generalises to human carriers of a missense allele, in whom the synapse is altered rather than absent, is unknown, and no DFNA25 implant outcome has been published.
Mechanism Target:
BYPASSES Failure of Auditory Nerve Activation with Preserved Cochlear Amplification — Direct electrical stimulation of the spiral ganglion substitutes for the defective inner hair cell synapse.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"although auditory brainstem responses could be elicited by electrical stimuli"
The preserved electrical responsiveness that an implant would exploit. Model evidence for a human intervention, so the claim in the description is plausibility rather than efficacy.
AAV-mediated VGLUT3 Gene Replacement
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Preclinical only, and preclinical in the null mouse rather than in an animal carrying a human allele. Cochlear delivery of AAV1-VGLUT3 normalises brainstem response thresholds within two weeks and partially reverses the ribbon synapse changes; delivery to five-week-old null mice with an AAV8 vector restored auditory function and recovered inner hair cells and stereocilia twenty-seven weeks later. Two things stand between this and DFNA25. The disease is dominant, so gene addition may not be the right strategy if the human allele acts by anything other than loss of function, and the mouse work is gene replacement into a null background. And no SLC17A8-specific human trial exists.
Mechanism Target:
RESTORES Altered VGLUT3 Function in the Inner Hair Cell — Restoring VGLUT3 protein to the inner hair cell addresses the molecular lesion rather than its consequences - in an animal that has none of the protein to begin with.
Show evidence (2 references)
PMID:22841313 SUPPORT Model Organism
"Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response."
The functional rescue, in the null mouse.
PMID:40841774 SUPPORT Model Organism
"Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy."
Rescue after the neonatal window, which is the version relevant to a postlingual human disease.
Show evidence (1 reference)
PMID:22841313 SUPPORT Model Organism
"These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness."
The authors' own framing of how far the result reaches - toward human therapy, not to it.
🔬

Diagnosis

2
Molecular testing of SLC17A8
The diagnosis is molecular and there is no audiometric finding that makes it without sequencing. SLC17A8 sits on comprehensive hereditary hearing-loss panels; in the reported families it has been reached by candidate-gene sequencing after linkage, by targeted screening of a dominant cohort, and by whole-exome sequencing. Because penetrance is age-dependent, testing an at-risk relative is more informative than audiometry.
Show evidence (2 references)
PMID:28647561 SUPPORT Human Clinical
"To identify a causative mutation of HL in this family, we performed whole-exome sequencing of 4 family members, 3 affected and an unaffected."
The exome route, in a family where linkage was not available.
PMID:26797701 SUPPORT Human Clinical
"In this study, we performed a genetic analysis of 87 unrelated Korean patients with ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean population."
The yield to expect from targeted screening: one novel frameshift across 87 unrelated dominant probands. SLC17A8 is a rare cause even within dominant nonsyndromic hearing loss.
Variant interpretation as a distinct problem in this gene
Several SLC17A8 variants reported as suspected causes have not been functionally confirmed, and a study set up to test two of them found they behave differently from each other: c.616dupA reduced both transcript and protein, while c.824C>A left transcript levels alone and produced an abnormal protein. Neither result is a segregation study, so the practical point is that an SLC17A8 variant list should not be read as a list of established mechanisms.
Show evidence (2 references)
PMID:34145196 SUPPORT In Vitro
"Although several suspected pathogenic mutations of the SLC17a8 gene have been identified in humans, few studies have confirmed their pathogenicity."
The interpretation problem stated by the authors as their motivation.
PMID:34145196 SUPPORT In Vitro
"The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this mutation did not affect the transcriptional..."
Two alleles in one gene with two different molecular consequences, measured in cell culture.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 25:

Presbycusis and noise-induced hearing loss
Overlapping Features The differential that matters, and the reason DFNA25 is probably underdiagnosed. A slowly progressive, bilateral, high-frequency sensorineural loss beginning in adult life is the audiometric signature of age-related and noise-related hearing loss, which are incomparably more common. The founding clinical study says separating them is difficult, and the gene paper opens by noting that dominant sensorineural hearing loss as a class closely resembles presbycusis. Family history across generations is the discriminator available without sequencing.
Show evidence (2 references)
PMID:12925340 SUPPORT Human Clinical
"It is difficult to differentiate delayed-onset high-frequency sensorineural hearing loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from that due to noise exposure or presbycusis, disorders that may also have a genetic component."
The difficulty stated as the study's own conclusion.
PMID:18674745 SUPPORT Human Clinical
"Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans."
The same resemblance stated for the dominant class DFNA25 belongs to.
🐁

Animal Models

2
Slc17a8 null mouse
The founding model and the source of the presynaptic mechanism. It establishes that the inner hair cell releases empty vesicles, that the cochlear amplifier and the ascending pathway are both intact, and that afferent synapses and spiral ganglion neurons are lost later. It also carries a phenotype the human disease does not have - a generalised epilepsy - reflecting VGLUT3's expression outside the ear.
Species
Mouse
Genotype
Slc17a8 (Vglut3) exon 2 targeted deletion, homozygous null
Publication
PMID:18674745
Pathograph links
Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse recapitulates fidelity: moderate The release failure and its localisation to vesicle content rather than fusion, both measured directly in the correct cell type.
Limitations: A homozygous constitutive null, whereas DFNA25 patients are heterozygous for a missense allele; heterozygous Slc17a8 knockout mice hear normally, so this animal does not model the dominant genetics of the human disease at all. It is congenitally and profoundly deaf where the patients are postlingual and progressive. The epilepsy is a mouse phenotype with no reported human counterpart.
Readouts
Calcium-triggered synaptic vesicle turnover in inner hair cells
Direction: UNCHANGED
Interpretation: Exocytosis itself is normal. A deliberate negative result, and the one that makes the defect a cargo defect rather than a release-machinery defect.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age."
The capacitance measurement behind this readout.
Ribbon synapse ultrastructure at three months
Direction: UNCHANGED
Interpretation: The surviving ribbon synapses are structurally normal, so at this age the lesion is functional rather than morphological.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance."
The electron-microscopy observation behind this readout.
Show evidence (1 reference)
PMID:18215623 SUPPORT Model Organism
"We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway."
Supports treating this model as informative for the release node.
Failure of Auditory Nerve Activation with Preserved Cochlear Amplification recapitulates fidelity: moderate The three-way dissociation - no acoustic neural response, intact emissions, intact electrically evoked brainstem response - measured in one animal.
Limitations: The human audiology contradicts half of it. Otoacoustic emissions are reported absent in p.A211V carriers, so the preserved-amplification half of this dissociation is a mouse result the patients do not reproduce, and the entry curates that as a separate phenotype. No electrically evoked brainstem response has been published for any DFNA25 patient. The mouse is also completely unresponsive to sound, whereas patients retain useful low-frequency hearing for decades.
Readouts
Otoacoustic emissions
Direction: UNCHANGED
Interpretation: Outer hair cell amplification is preserved, placing the lesion downstream of the cochlear amplifier. A negative result, and the load-bearing one.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"robust otoacoustic emissions were recorded"
The emissions measurement behind this readout.
Electrically evoked auditory brainstem response
Direction: UNCHANGED
Interpretation: The ascending auditory pathway can still be driven when the defective synapse is bypassed, which is the observation that makes cochlear implantation biologically plausible in this disease.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"although auditory brainstem responses could be elicited by electrical stimuli"
The electrical-stimulation measurement behind this readout.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded."
Supports treating this model as informative for the dissociation node.
Secondary Deafferentation of the Inner Hair Cell recapitulates fidelity: low The afferent synapses, spiral ganglion neurons and lateral efferent endings decline after the functional deficit is established.
Limitations: Fidelity is LOW because the timing cannot transfer. This animal never hears, so its deafferentation follows a complete congenital absence of afferent drive; DFNA25 patients hear normally for decades first. Part of the loss is attributed to a developmental role for hair-cell glutamate before hearing onset, a window that has already closed by the time a human carrier becomes symptomatic. No human temporal-bone or synapse-count data exist for comparison.
Readouts
Afferent synapse and spiral ganglion neuron counts
Direction: DECREASED
Interpretation: The afferent population beneath the inner hair cell falls over time in the null animal.
Show evidence (1 reference)
PMID:18674745 SUPPORT Model Organism
"Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined."
The counting result behind this readout.
Show evidence (1 reference)
PMID:18215623 SUPPORT Model Organism
"The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing."
Supports the model for this node while naming the developmental confound that limits its fidelity.
VGLUT3 A224V knock-in mouse
The allele-matched model, and the reason this entry carries two hypothesis groups. A single point mutation was introduced into exon 5 of mouse Slc17a8, exchanging the codon for the alanine that corresponds to human A211. It reproduces the progressive course the null mouse does not, and it reaches a different conclusion about where the disease starts.
Species
Mouse
Genotype
Slc17a8 p.A224V knock-in (mouse equivalent of human p.A211V), homozygous
Publication
PMID:34783032
Pathograph links
Inner Hair Cell Stereocilia Bundle Disruption recapitulates fidelity: moderate Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell bundles spared - the model's primary structural finding.
Limitations: Homozygous for an allele that patients carry heterozygously, so the model may be reporting a dose effect that heterozygous carriers never reach. Whether human DFNA25 inner hair cells have disordered bundles is unknown and unknowable in life. The paper offers no mechanism connecting the transporter to bundle architecture, so this remains a correlation within the model.
Readouts
Inner hair cell stereocilia bundle morphology by scanning electron microscopy
Direction: ALTERED
Interpretation: Inner hair cell bundles collapse; outer hair cell bundles do not. The contrast within the same cochlea is what makes this a cell-type-specific lesion rather than general degeneration.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected."
The microscopy result behind this readout.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"These results suggest that DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer."
The authors' claim that this model's structural finding is the disease's starting point, which is what makes the model informative for this node.
Reduced Inner Hair Cell Receptor Potential recapitulates fidelity: moderate The functional counterpart of the bundle collapse, measured as a reduced summating potential in an animal whose cochlear amplifier is intact.
Limitations: The summating potential is a gross cochlear potential and an indirect index of the inner hair cell receptor potential rather than a recording from the cell. It is not measured clinically in DFNA25 patients, so there is no human comparison.
Readouts
Summating potential
Direction: DECREASED
Interpretation: A smaller receptor-potential correlate from a mechanically normal input, consistent with a transduction rather than an amplification deficit.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential."
The measurement behind this readout.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"The VGLUT3A224V/A224V mouse model opens the way to a deeper understanding and to a potential treatment for DFNA25."
The authors' framing of the model as the system for studying this disease.
Synaptic Ribbon Enlargement and Altered Sustained Exocytosis recapitulates fidelity: moderate Oversized ribbons and a faster sustained release rate, appearing later than the transduction findings.
Limitations: The direction is opposite to the null mouse, where ribbons are described as abnormally thin and elongated, so the two models disagree about ribbon morphology as well as about the order of events. Whether the change is compensatory or injurious is untested, and no human ribbon data exist.
Readouts
Synaptic ribbon size by super-resolution microscopy
Direction: INCREASED
Interpretation: Ribbons are larger than wild type in the knock-in animal.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"Using super-resolution microscopy, we observed oversized synaptic ribbons and patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis."
The imaging result behind this readout.
Sustained releasable pool exocytosis rate
Direction: INCREASED
Interpretation: Sustained release is faster, not slower. This is the finding that makes the knock-in a model of altered rather than failed synaptic transfer.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis"
The capacitance measurement behind this readout.
Show evidence (1 reference)
PMID:34783032 SUPPORT Model Organism
"In addition, IHC ribbon synapses underwent structural and functional modifications at later stages."
Supports the model for this node and fixes its position late in the sequence.
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 25
creation_date: "2026-09-01T20:30:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 25
  term:
    id: MONDO:0011568
    label: autosomal dominant nonsyndromic hearing loss 25
synonyms:
- DFNA25
- deafness, autosomal dominant 25
- autosomal dominant nonsyndromic deafness 25
- SLC17A8 autosomal dominant nonsyndromic deafness
- autosomal dominant nonsyndromic deafness caused by mutation in SLC17A8
description: >-
  Delayed-onset, progressive, predominantly high-frequency sensorineural hearing loss caused
  by heterozygous variants in SLC17A8, which encodes vesicular glutamate transporter 3
  (VGLUT3). VGLUT3 is the transporter that fills the synaptic vesicles of the cochlear inner
  hair cell with glutamate before they are released onto the auditory nerve terminal, so the
  gene sits at the very first synapse of hearing. Among the three vesicular glutamate
  transporters it is the only one expressed in inner hair cells, which is why a defect in it
  produces deafness and almost nothing else.

  Two things make this entry worth reading rather than filing as one more DFNA locus.

  The first is that the gene's function makes DFNA25 look like an auditory synaptopathy and
  the patients do not behave like one. The Slc17a8 null mouse is a textbook synaptopathy:
  otoacoustic emissions are robust, sound-evoked auditory-nerve responses are absent, and
  brainstem responses can still be driven electrically, so the cochlear amplifier is intact
  and the step after it is not. The knock-in mouse carrying the actual human allele has intact
  emissions too. But in the patients carrying that same allele, otoacoustic emissions are
  absent - the opposite result - and the knock-in study concludes on that basis that DFNA25 is
  more likely a progressive hearing loss than an auditory neuropathy. Whether those absent
  emissions are the disease or a lifetime of accumulated noise exposure is unresolved, and it
  is the question that decides which class this disease belongs to.

  The second is that the two mouse models disagree about where the lesion starts. The null
  points at vesicle filling. The knock-in points at the hair bundle: inner hair cell
  stereocilia collapse while outer hair cell bundles do not, the summating potential falls,
  and the synaptic changes - oversized ribbons, a faster sustained release rate - appear
  later. That is mechanistically surprising, because VGLUT3 is not present in inner hair cell
  stereocilia and its loss does not affect transducer activity, so no route from the
  transporter to the bundle is established. This entry curates both accounts as hypothesis
  groups rather than choosing between them.

  The third is that neither mouse has the genotype a patient has. Both are homozygous. The
  heterozygous knock-in - the genotype that matches a DFNA25 carrier - has only mild hearing
  impairment, which its authors note contrasts with the dominant transmission seen in the
  human families. Because truncating and splice alleles have since been reported in dominant
  families too, the allelic mechanism has to be argued case by case rather than assumed from
  the gene.

  Clinically the disease is easy to miss. It is postlingual, slowly progressive and
  high-frequency, which is the audiometric shape of presbycusis and of noise damage, and the
  founding clinical study says in as many words that separating it from those is difficult.
  Penetrance is age-dependent and, in the original kindred, appeared to depend on which
  parent transmitted the haplotype.
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
- Hereditary Hearing Loss

external_assertions:
- name: ClinGen SLC17A8-nonsyndromic hearing loss gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  description: >-
    The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal dominant
    SLC17A8-nonsyndromic hearing loss relationship as Definitive. The classification was
    raised from Strong in 2018 to Definitive in 2023 on additional case-level evidence, and
    the panel's own count of the evidence base - nine probands, eight variants, twenty-eight
    additional segregating relatives - is the best available statement of how small this
    disease's human literature is.
  evidence:
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC17A8 | HGNC:20151 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Definitive"
    explanation: >-
      The expert-panel classification row itself, with gene, disease, inheritance mode and
      verdict.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At least 8 unique variants (missense, frameshift, splice site) have been reported in
      humans in 9 probands
    explanation: >-
      The size of the human evidence base, which is the number every frequency and prevalence
      statement in this entry has to be read against.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As a result of this reevaluation, the classification increased from Strong to
      Definitive due to additional case level evidence
    explanation: >-
      Records that the Definitive verdict is recent and was reached by upgrade, not asserted
      at first curation.

mechanistic_hypotheses:
- hypothesis_group_id: presynaptic_glutamate_loading_failure
  hypothesis_label: Presynaptic vesicular glutamate loading failure
  status: CANONICAL
  description: >-
    The account that follows from what VGLUT3 does. Without the transporter the inner hair
    cell still fuses vesicles on schedule, but the vesicles are empty, so the auditory nerve
    is never driven while the outer hair cells keep amplifying. This is what the Slc17a8 null
    mouse shows and it is the reason DFNA25 is discussed alongside the auditory
    synaptopathies. It has two limitations. The null mouse is homozygous and congenitally
    deaf, whereas DFNA25 patients are heterozygous and lose hearing slowly in adult life. And
    the audiological prediction it makes - preserved otoacoustic emissions - is contradicted
    in the patients, whose emissions are absent. It is kept as the canonical group because it
    is what the transporter does and what the null animal shows, not because the human
    audiology supports it.
- hypothesis_group_id: a211v_mechanotransduction_first
  hypothesis_label: Stereociliary mechanotransduction failure preceding synaptic change
  status: EMERGING
  description: >-
    The account that follows from the mouse carrying the human allele rather than a deletion.
    In the VGLUT3 A224V knock-in the inner hair cell hair bundles collapse and the summating
    potential - the receptor potential of the inner hair cell - falls, while cochlear
    amplification stays intact; the ribbon changes come afterwards. On this reading the
    primary lesion in DFNA25 is the transduction apparatus and the synapse is a downstream
    casualty, which would place the disease outside the synaptopathies rather than inside
    them. It is one model, homozygous for an allele patients carry heterozygously, so this is
    recorded as emerging rather than established.

pathophysiology:

- name: Heterozygous SLC17A8 Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The founding and best-characterised allele is the missense c.632C>T, p.A211V, which
    segregated with deafness in two apparently unrelated families sharing a distant common
    ancestor and was absent from 267 controls. The alanine is conserved across species and
    across all three human VGLUT paralogues.

    Later reported dominant alleles are of a different kind: a frameshift, p.M206Nfs*4,
    predicted to truncate the protein at residue 209 and remove transmembrane domains 5 to
    12, and a canonical splice-donor variant, c.763+1G>T. Whether these act by the same
    route as the missense allele is not established, and the entry does not assume it.
  genetic_context:
    gene:
      preferred_term: SLC17A8
      term:
        id: hgnc:20151
        label: SLC17A8
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous in every reported family. `functional_impact_category` is deliberately
      left empty: heterozygous Slc17a8 knockout mice hear normally while heterozygous human
      p.A211V carriers do not, so the missense allele is not behaving as a simple
      loss-of-function, and no dominant-negative or gain-of-function experiment has been
      done to license one of the narrower values instead. The truncating and splice alleles
      may well be loss-of-function, but they sit in the same slot on the same node and the
      category is single-valued.
  downstream:
  - target: Altered VGLUT3 Function in the Inner Hair Cell
    causal_link_type: DIRECT
    description: >-
      Every proposed mechanism for this disease runs through the transporter that the
      variant sits in.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was
      found to segregate with DFNA25 deafness and was not present in 267 controls.
    explanation: >-
      The founding allele, its zygosity, its segregation and its control screening.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes
      (VGLUT1-3), suggesting an important functional role.
    explanation: >-
      The conservation argument the founding paper rests the missense call on.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to
      asparagine at amino acid position 206, resulted in a termination codon at amino acid
      position 209.
    explanation: >-
      A truncating dominant allele, structurally quite unlike the founding missense.
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel splicing mutation, c.763+1G>T, in the solute carrier family 17, member 8
      (SLC17A8) gene was identified in the patients, and the genotypes of the mutation were
      co-segregated with the phenotype of HL.
    explanation: >-
      The splice-donor allele and its co-segregation in a three-generation dominant family.

- name: Altered VGLUT3 Function in the Inner Hair Cell
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    VGLUT3 is the vesicular glutamate transporter of the cochlear inner hair cell: it
    accumulates glutamate inside the synaptic vesicle so that the vesicle has something to
    release when it fuses. Of the three VGLUT paralogues it is the only one selectively
    expressed in inner hair cells, which is why the cochlear phenotype is not compensated by
    VGLUT1 or VGLUT2 and why an otherwise widely expressed transporter gives a nonsyndromic
    deafness.

    What the human p.A211V substitution does to that function is the open part. It does not
    impair vesicular glutamate accumulation, quantal release or quantal content when tested
    in hippocampal autaptic neurons, and in the knock-in mouse it lowers VGLUT3 protein in
    central terminals by roughly seventy per cent without changing VGLUT3-dependent
    behaviour. So the allele is not a straightforward transport-dead mutant, and the two
    hypothesis groups below diverge from this node rather than from the variant.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  molecular_functions:
  - preferred_term: vesicular L-glutamate transport by VGLUT3
    modifier: DECREASED
    term:
      id: GO:0005313
      label: L-glutamate transmembrane transporter activity
  biological_processes:
  - preferred_term: glutamate loading into inner hair cell synaptic vesicles
    modifier: DECREASED
    term:
      id: GO:0098700
      label: neurotransmitter loading into synaptic vesicle
  cellular_components:
  - preferred_term: inner hair cell synaptic vesicle
    term:
      id: GO:0008021
      label: synaptic vesicle
  downstream:
  - target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
    causal_link_type: DIRECT
    hypothesis_groups:
    - presynaptic_glutamate_loading_failure
    description: >-
      The direct consequence of an unfilled vesicle, and the route the null mouse takes.
  - target: Inner Hair Cell Stereocilia Bundle Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no
      mechanism connecting an altered vesicular transporter to hair-bundle architecture has
      been demonstrated; the knock-in shows the bundles collapse, not why.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory
      inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals.
    explanation: >-
      The normal function of the protein, which is what the disease removes or alters.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair
      cells (IHCs)
    explanation: >-
      Why there is no paralogue to compensate in the inner hair cell, and therefore why the
      phenotype is cochlear and nonsyndromic.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This variation does not impair the glutamate vesicular accumulation, neither the
      quantal release nor the quantal content in hippocampal autaptic neurons
    explanation: >-
      A negative result at the level of transport itself, which is why this entry does not
      assert that the human missense allele simply stops glutamate loading. Graded IN_VITRO
      because the measurement is in cultured autaptic neurons.

- name: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
  biological_scale: CELLULAR
  description: >-
    In the Slc17a8 null cochlea the machinery of release is intact and the cargo is not.
    Calcium-triggered vesicle turnover measured by membrane capacitance is normal at two
    weeks of age, and the ribbon synapses that survive to three months look normal under the
    electron microscope. What is missing is the glutamate, so the vesicles fuse and the
    afferent terminal is not driven.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: glutamate secretion at the inner hair cell afferent synapse
    modifier: DECREASED
    term:
      id: GO:0014047
      label: glutamate secretion
  downstream:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    causal_link_type: DIRECT
    hypothesis_groups:
    - presynaptic_glutamate_loading_failure
    description: >-
      An afferent terminal that receives no transmitter does not fire, however well the
      cochlea in front of it is working.
  evidence:
  - reference: PMID:18215623
    reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of
      glutamate release from hair cells at the first synapse in the auditory pathway.
    explanation: >-
      The release failure stated directly, and its location at the first auditory synapse.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when
      probed by membrane capacitance measurements at 2 weeks of age.
    explanation: >-
      The deliberate negative result that localises the defect to vesicle content rather than
      to exocytosis. Without it the node would be indistinguishable from a fusion defect.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of
      vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding
      at the IHC synapse.
    explanation: >-
      The founding paper's own conclusion about the null animal.

- name: Inner Hair Cell Stereocilia Bundle Disruption
  biological_scale: CELLULAR
  description: >-
    In the knock-in mouse carrying the human allele, scanning electron microscopy shows the
    inner hair cell stereocilia bundles collapsing and fusing while the outer hair cell
    bundles are left alone. That selectivity matters: it is the same cell-type restriction as
    the transporter's expression, and it means the finding is not general hair-cell
    degeneration.

    No mechanism links a vesicular glutamate transporter to hair-bundle architecture, and the
    finding is surprising on its own terms: VGLUT3 is not present in inner hair cell
    stereocilia, and losing VGLUT3 altogether leaves the transducer working, with an intact
    hair cell receptor potential. The paper's own candidate explanation - that the variant
    protein misfolds and aggregates, disrupting traffic towards the stereocilia machinery - is
    argued against by two earlier results it cites: the point mutation reduces VGLUT3 in nerve
    terminals while leaving the soma unchanged, and a structural model shows that swapping
    alanine for valine barely changes the protein. The node is curated because the
    allele-matched model reports it as the primary lesion, not because the connection is
    understood.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: inner hair cell stereocilium bundle organization
    modifier: DECREASED
    term:
      id: GO:0060122
      label: inner ear receptor cell stereocilium organization
  downstream:
  - target: Reduced Inner Hair Cell Receptor Potential
    causal_link_type: DIRECT
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      A collapsed bundle is a bundle that transduces less, and the summating potential falls
      in the same animals.
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Scanning electron microscopy examinations demonstrated the collapse of stereocilia
      bundles in IHCs, leaving those from outer hair cells unaffected.
    explanation: >-
      The bundle finding and its restriction to inner hair cells.

- name: Reduced Inner Hair Cell Receptor Potential
  biological_scale: CELLULAR
  description: >-
    The summating potential is the gross cochlear correlate of the inner hair cell receptor
    potential, and it is reduced in the knock-in mouse. Because cochlear amplification is
    intact in the same animals, a smaller receptor potential is being generated from a normal
    mechanical input - which is what a transduction defect in the inner hair cell looks like
    from outside.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: mechanotransduction in the inner hair cell hair bundle
    modifier: DECREASED
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
  downstream:
  - target: Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      The knock-in paper orders these two findings in time - transduction first, synaptic
      change later - so the edge records a sequence the model establishes rather than a
      demonstrated causal step.
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    causal_link_type: DIRECT
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      A receptor potential that does not reach normal amplitude drives less transmitter
      release, whatever state the vesicles are in.
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The summating potential was reduced, indicating the alteration of inner hair cell (IHC)
      receptor potential.
    explanation: >-
      The measurement and the authors' own interpretation of it.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that DFNA25 stems from a failure in the mechano-transduction
      followed by a change in synaptic transfer.
    explanation: >-
      The ordering claim that this hypothesis group is built on, stated by the authors as a
      suggestion rather than a demonstration - which is why the group is EMERGING.

- name: Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
  biological_scale: CELLULAR
  description: >-
    Later in the knock-in mouse the ribbons grow oversized and the rate of sustained
    releasable pool exocytosis rises. This is a change in synaptic transfer rather than a
    loss of it, and it points the same way as the null mouse's ribbon morphology, where
    ribbons are described as abnormally thin and elongated. Whether an enlarged ribbon with a
    faster sustained release rate is compensatory or maladaptive has not been tested.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: sustained glutamate release from the inner hair cell ribbon synapse
    modifier: INCREASED
    term:
      id: GO:0014047
      label: glutamate secretion
  downstream:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      Altered rather than absent transfer, in an animal whose brainstem responses are
      progressively lost. The link is INDIRECT because the paper does not show that the
      ribbon change is what degrades the response.
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using super-resolution microscopy, we observed oversized synaptic ribbons and
      patch-clamp membrane capacitance measurements showed an increase in the rate of the
      sustained releasable pool exocytosis.
    explanation: >-
      Both halves of this node, measured directly.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, IHC ribbon synapses underwent structural and functional modifications at
      later stages.
    explanation: >-
      The timing, which is what makes this node downstream of the transduction node rather
      than parallel to it.

- name: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
  biological_scale: TISSUE
  description: >-
    The convergence point of both hypothesis groups, and the finding that puts DFNA25 in the
    same conversation as the auditory synaptopathies - in the models, at least. In the null
    mouse, sound-evoked
    auditory-nerve responses are absent while otoacoustic emissions are robust, and brainstem
    responses can still be evoked electrically - so the cochlear amplifier and the ascending
    pathway both work and the step between them does not. In the knock-in mouse the same
    dissociation appears in progressive form: brainstem responses deteriorate with age while
    distortion-product emissions stay intact.

    This is a mouse finding, and in the patients it does not hold. Otoacoustic emissions are
    reported absent in carriers of the p.A211V allele - the opposite of both mice - which is
    why the knock-in study concludes that DFNA25 in humans is more likely a progressive
    hearing loss than an auditory neuropathy. The node is therefore curated as what the models
    show, not as a human phenotype, and the absent-emissions finding is curated separately
    under phenotypes.
  cell_types:
  - preferred_term: type 1 spiral ganglion neuron
    term:
      id: CL:4023115
      label: type 1 spiral ganglion neuron
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  locations:
  - preferred_term: organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  downstream:
  - target: Secondary Deafferentation of the Inner Hair Cell
    causal_link_type: DIRECT
    description: >-
      An afferent synapse that is never driven does not survive indefinitely, and in the null
      mouse the synapses, the neurons and the efferent endings all decline later.
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      The clinical phenotype is what an auditory nerve that is inadequately driven produces.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to
      acoustic stimuli, although auditory brainstem responses could be elicited by electrical
      stimuli, and robust otoacoustic emissions were recorded.
    explanation: >-
      All three halves of the dissociation in one sentence: no acoustic neural response,
      preserved electrical response, preserved emissions.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using auditory brainstem response and distortion product otoacoustic emissions, we
      showed progressive hearing loss with intact cochlear amplification in the
      VGLUT3A224V/A224V mouse.
    explanation: >-
      The same dissociation in the allele-matched model, and in progressive rather than
      congenital form.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decent DPOAEs were recorded in the knock-in mutant mouse. In contrast, otoacoustic
      emissions were absent in patients harbouring the p.A211V allele
    explanation: >-
      Refutes this node as a human phenotype. The preserved-amplification half of the
      dissociation is a mouse result that the patients contradict, which is the single most
      important qualification on this entry. Graded HUMAN_CLINICAL because the quoted clause
      reports a patient audiological finding, even though the paper is otherwise a mouse study.

- name: Secondary Deafferentation of the Inner Hair Cell
  biological_scale: TISSUE
  description: >-
    In the null mouse the afferent synapses beneath the inner hair cells, the spiral ganglion
    neurons themselves and the lateral efferent endings all decline with time, and some
    cochlear ganglion neurons degenerate early enough that the glutamate released before
    hearing onset is inferred to have a developmental role rather than only a signalling one.
    Aged null cochleae show degeneration of inner hair cells, synapses and stereocilia
    together.

    This matters clinically because it is the part of the disease a therapy would have to
    outrun.
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  downstream:
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Loss of the afferent population adds an irreversible component to a deficit that began
      as a functional one.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent
      endings below sensory IHCs declined.
    explanation: >-
      The deafferentation itself, and its late timing relative to the functional deficit.
  - reference: PMID:18215623
    reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The early degeneration of some cochlear ganglion neurons in knockout mice also
      indicates an important developmental role for the glutamate released by hair cells
      before the onset of hearing.
    explanation: >-
      The developmental component, which is a different claim from use-dependent loss and is
      the reason a congenital null and an adult-onset human disease may diverge here.
  - reference: PMID:40841774
    reference_title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing
      significant degeneration of inner hair cells, synapses, and stereocilia.
    explanation: >-
      The structural endpoint in the aged null animal.

phenotypes:

- category: Otologic
  name: Progressive High-Frequency Sensorineural Hearing Loss
  description: >-
    The defining phenotype: bilateral sensorineural loss that begins at high frequencies and
    worsens slowly over years. It was the phenotype the locus was mapped on, before the gene
    was known, in a large multigenerational United States family of Czech descent.

    No frequency band is asserted. The published human material is nine probands across
    eight variants, and no series has reported what proportion of carriers show a given
    audiometric feature, so any band here would be a number invented for the slot.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11115382
    reference_title: "DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a novel dominant locus, DFNA25, for delayed-onset, progressive,
      high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational
      United States family of Czech descent.
    explanation: >-
      The phenotype as defined at the locus, in the founding kindred.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified SLC17A8, which encodes the vesicular glutamate transporter-3
      (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of
      progressive, high-frequency nonsyndromic deafness.
    explanation: >-
      The same phenotype restated once the gene was in hand.

- category: Otologic
  name: Postlingual Delayed Onset
  description: >-
    Hearing is normal through speech acquisition and the loss declares itself later. In the
    original kindred the clinical study describes onset in the postlingual period, and the
    linkage report calls the phenotype delayed-onset. This is what separates DFNA25 from the
    prelingual recessive deafnesses and puts it outside the newborn screening window.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals typically manifest a high-frequency, slowly progressive
      sensorineural hearing loss in the postlingual period.
    explanation: >-
      Onset timing, from the serial-audiogram study of the founding family.

- category: Otologic
  name: Age-Dependent Penetrance
  description: >-
    Carriers are not uniformly affected at any given age; the proportion affected rises with
    age. The founding clinical study additionally reports a parent-of-origin pattern in that
    single family - carriers who inherited the haplotype from an affected mother were
    invariably affected by the second decade, while those who inherited it from an affected
    father often had age-normal hearing into the seventh decade - and a sex difference in
    reported onset, males earlier than females.

    Both of those observations come from one kindred, were made before the gene was
    identified, and have not been replicated. They are recorded because they are the only
    published statements about penetrance in this disease, not because they are established.
    The same study screened four deafness-associated mitochondrial variants in the family and
    found none segregating, so a mitochondrial explanation for the maternal pattern was
    looked for and not found.

    No phenotype_term is bound. The obvious candidate, HP:0003829 Typified by incomplete
    penetrance, is an HPO clinical modifier rather than a phenotypic abnormality and is not
    a member of the PhenotypeTerm enum, so binding it would fail term validation; nothing in
    the phenotypic-abnormality branch expresses age-dependent penetrance.
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mode of inheritance is autosomal dominant with age-dependent penetrance.
    explanation: >-
      The penetrance statement itself.
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those inheriting the DFNA25-associated haplotype from an affected mother, hearing
      loss invariably developed by the second decade of life, whereas those inheriting the
      DFNA25 haplotype from an affected father often maintained hearing levels comparable to
      those of age-matched control subjects, even into the seventh decade of life.
    explanation: >-
      The parent-of-origin observation, quoted in full so the size and source of the claim
      travel with it.
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G,
      Cins7472, and 7511T>C) were found to segregate in the family.
    explanation: >-
      Records that the obvious maternal-transmission explanation was tested and excluded in
      this family.

- category: Otologic
  name: Absent Otoacoustic Emissions
  description: >-
    Otoacoustic emissions are reported absent in patients carrying the p.A211V allele. This is
    the single most consequential human finding in the entry, and it points away from the class
    the gene's function would predict: an auditory synaptopathy has preserved emissions with an
    absent or desynchronised brainstem response, and these patients do not. On that basis the
    knock-in study concludes DFNA25 is more likely a progressive hearing loss than an auditory
    neuropathy.

    Two readings are open, and the source raises both. Absent emissions may mean the outer hair
    cells are involved, which would place the lesion outside the synapse. Or they may reflect
    accumulated noise exposure over a lifetime in a middle-aged cohort, which would be an
    acquired overlay on a synaptopathic disease. Nobody has separated these, and the entry does
    not choose.

    No frequency band is given. The observation reaches this entry as a statement about "patients
    harbouring the p.A211V allele" in a later paper's discussion, without a numerator, and the
    primary audiological study it points to is a single family.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, otoacoustic emissions were absent in patients harbouring the p.A211V allele
    explanation: >-
      The human audiological finding itself. Graded HUMAN_CLINICAL because the clause reports a
      patient measurement, although the paper it appears in is a mouse study.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, DFNA25 is more likely to be a progressive hearing loss in human rather than an
      auditory neuropathy
    explanation: >-
      The classification conclusion the authors draw from it, which is the reason this entry does
      not file DFNA25 under the auditory neuropathy spectrum.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lack of otoacoustic emissions in DFNA25 patients might be due to additional factors
      encountered during lifetime such as noise
    explanation: >-
      The competing explanation, offered by the same authors as a possibility they did not test.
      Graded NO_EVIDENCE because it reports a hypothesis rather than a result, and it is the
      reason the classification above is recorded as a conclusion rather than as settled.

- category: Otologic
  name: Absence of Syndromic Features
  description: >-
    No consistent extra-auditory finding has been reported. A three-generation Korean family
    with the splice-donor allele is explicitly described as having no accompanying symptoms.

    There is a mechanistic reason to expect the vestibular system in particular to be spared
    even though VGLUT3 is present in vestibular hair cells: in the null mouse, quantal
    transmission in the utricular calyx collapses by more than ninety-five per cent while
    vestibular nerve firing and balance behaviour stay normal, because non-quantal
    transmission carries the type I hair cell synapse. The cochlea has no such backup.
  evidence:
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical information about this family revealed that there are no other symptoms
      accompanied with HL
    explanation: >-
      The nonsyndromic statement in a reported dominant family.
  - reference: PMID:41279968
    reference_title: Persistence of vestibular function in the absence of glutamatergic transmission from hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In behavioral studies, Vglut3 -/- mice did not exhibit considerable sensorimotor or
      balance deficits.
    explanation: >-
      Vestibular sparing in the model, which is why the human phenotype being purely cochlear
      is expected rather than surprising.
  - reference: PMID:41279968
    reference_title: Persistence of vestibular function in the absence of glutamatergic transmission from hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Collectively, these data support the view that non-quantal transmission is the
      predominant mode of neurotransmission between type I VHCs and vestibular calyceal
      afferent neurons.
    explanation: >-
      The mechanism of the sparing - a parallel transmission mode that the cochlear afferent
      synapse does not have.

genetic:

- name: SLC17A8
  gene_term:
    preferred_term: SLC17A8
    term:
      id: hgnc:20151
      label: SLC17A8
  relationship_type: CAUSATIVE
  notes: >-
    The single causal gene, encoding vesicular glutamate transporter 3. Eight unique variants
    across nine probands were on ClinGen's count at the 2023 reevaluation - missense,
    frameshift and splice site - with twenty-eight further segregating relatives in two
    families.

    The alleles are not obviously one mechanism. p.A211V is a conserved missense that leaves
    vesicular glutamate accumulation intact where it has been tested; p.M206Nfs*4 and
    c.763+1G>T predict a truncated or absent product. The entry keeps them together as one
    causative gene record and does not claim a shared molecular route.
  evidence:
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in this gene segregated with disease in 28 additional members in two families
    explanation: >-
      The segregation evidence behind the Definitive classification.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, SCL17A8 is definitively associated with autosomal dominant nonsyndromic
      hearing loss.
    explanation: >-
      The panel's summary sentence. The gene symbol is transposed in the source record and is
      quoted as written.

inheritance:

- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Every reported proband is heterozygous and the trait segregates vertically through
    multiple generations. Penetrance is age-dependent, so an unaffected young carrier does
    not exclude the diagnosis and phenotype-based testing of relatives is unreliable.
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mode of inheritance is autosomal dominant with age-dependent penetrance.
    explanation: >-
      Inheritance mode and the penetrance qualifier together.

animal_models:

- name: Slc17a8 null mouse
  species: Mouse
  genotype: Slc17a8 (Vglut3) exon 2 targeted deletion, homozygous null
  publication: PMID:18674745
  description: >-
    The founding model and the source of the presynaptic mechanism. It establishes that the
    inner hair cell releases empty vesicles, that the cochlear amplifier and the ascending
    pathway are both intact, and that afferent synapses and spiral ganglion neurons are lost
    later. It also carries a phenotype the human disease does not have - a generalised
    epilepsy - reflecting VGLUT3's expression outside the ear.
  modeled_mechanisms:
  - target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The release failure and its localisation to vesicle content rather than fusion, both
      measured directly in the correct cell type.
    limitations: >-
      A homozygous constitutive null, whereas DFNA25 patients are heterozygous for a missense
      allele; heterozygous Slc17a8 knockout mice hear normally, so this animal does not model
      the dominant genetics of the human disease at all. It is congenitally and profoundly
      deaf where the patients are postlingual and progressive. The epilepsy is a mouse
      phenotype with no reported human counterpart.
    readouts:
    - name: Calcium-triggered synaptic vesicle turnover in inner hair cells
      target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
      direction: UNCHANGED
      interpretation: >-
        Exocytosis itself is normal. A deliberate negative result, and the one that makes the
        defect a cargo defect rather than a release-machinery defect.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice
          when probed by membrane capacitance measurements at 2 weeks of age.
        explanation: >-
          The capacitance measurement behind this readout.
    - name: Ribbon synapse ultrastructure at three months
      target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
      direction: UNCHANGED
      interpretation: >-
        The surviving ribbon synapses are structurally normal, so at this age the lesion is
        functional rather than morphological.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ribbon synapses remaining by 3 months of age had a normal ultrastructural
          appearance.
        explanation: >-
          The electron-microscopy observation behind this readout.
    evidence:
    - reference: PMID:18215623
      reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of
        glutamate release from hair cells at the first synapse in the auditory pathway.
      explanation: >-
        Supports treating this model as informative for the release node.
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The three-way dissociation - no acoustic neural response, intact emissions, intact
      electrically evoked brainstem response - measured in one animal.
    limitations: >-
      The human audiology contradicts half of it. Otoacoustic emissions are reported absent in
      p.A211V carriers, so the preserved-amplification half of this dissociation is a mouse
      result the patients do not reproduce, and the entry curates that as a separate phenotype.
      No electrically evoked brainstem response has been published for any DFNA25 patient. The
      mouse is also completely unresponsive to sound, whereas patients retain useful
      low-frequency hearing for decades.
    readouts:
    - name: Otoacoustic emissions
      target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
      direction: UNCHANGED
      interpretation: >-
        Outer hair cell amplification is preserved, placing the lesion downstream of the
        cochlear amplifier. A negative result, and the load-bearing one.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          robust otoacoustic emissions were recorded
        explanation: >-
          The emissions measurement behind this readout.
    - name: Electrically evoked auditory brainstem response
      target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
      direction: UNCHANGED
      interpretation: >-
        The ascending auditory pathway can still be driven when the defective synapse is
        bypassed, which is the observation that makes cochlear implantation biologically
        plausible in this disease.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          although auditory brainstem responses could be elicited by electrical stimuli
        explanation: >-
          The electrical-stimulation measurement behind this readout.
    evidence:
    - reference: PMID:18674745
      reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses
        to acoustic stimuli, although auditory brainstem responses could be elicited by
        electrical stimuli, and robust otoacoustic emissions were recorded.
      explanation: >-
        Supports treating this model as informative for the dissociation node.
  - target: Secondary Deafferentation of the Inner Hair Cell
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      The afferent synapses, spiral ganglion neurons and lateral efferent endings decline
      after the functional deficit is established.
    limitations: >-
      Fidelity is LOW because the timing cannot transfer. This animal never hears, so its
      deafferentation follows a complete congenital absence of afferent drive; DFNA25 patients
      hear normally for decades first. Part of the loss is attributed to a developmental role
      for hair-cell glutamate before hearing onset, a window that has already closed by the
      time a human carrier becomes symptomatic. No human temporal-bone or synapse-count data
      exist for comparison.
    readouts:
    - name: Afferent synapse and spiral ganglion neuron counts
      target: Secondary Deafferentation of the Inner Hair Cell
      direction: DECREASED
      interpretation: >-
        The afferent population beneath the inner hair cell falls over time in the null
        animal.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Later, the number of afferent synapses, spiral ganglion neurons, and lateral
          efferent endings below sensory IHCs declined.
        explanation: >-
          The counting result behind this readout.
    evidence:
    - reference: PMID:18215623
      reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The early degeneration of some cochlear ganglion neurons in knockout mice also
        indicates an important developmental role for the glutamate released by hair cells
        before the onset of hearing.
      explanation: >-
        Supports the model for this node while naming the developmental confound that limits
        its fidelity.

- name: VGLUT3 A224V knock-in mouse
  species: Mouse
  genotype: Slc17a8 p.A224V knock-in (mouse equivalent of human p.A211V), homozygous
  publication: PMID:34783032
  description: >-
    The allele-matched model, and the reason this entry carries two hypothesis groups. A
    single point mutation was introduced into exon 5 of mouse Slc17a8, exchanging the codon
    for the alanine that corresponds to human A211. It reproduces the progressive course the
    null mouse does not, and it reaches a different conclusion about where the disease starts.
  modeled_mechanisms:
  - target: Inner Hair Cell Stereocilia Bundle Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell
      bundles spared - the model's primary structural finding.
    limitations: >-
      Homozygous for an allele that patients carry heterozygously, so the model may be
      reporting a dose effect that heterozygous carriers never reach. Whether human DFNA25
      inner hair cells have disordered bundles is unknown and unknowable in life. The paper
      offers no mechanism connecting the transporter to bundle architecture, so this remains
      a correlation within the model.
    readouts:
    - name: Inner hair cell stereocilia bundle morphology by scanning electron microscopy
      target: Inner Hair Cell Stereocilia Bundle Disruption
      direction: ALTERED
      interpretation: >-
        Inner hair cell bundles collapse; outer hair cell bundles do not. The contrast within
        the same cochlea is what makes this a cell-type-specific lesion rather than general
        degeneration.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Scanning electron microscopy examinations demonstrated the collapse of stereocilia
          bundles in IHCs, leaving those from outer hair cells unaffected.
        explanation: >-
          The microscopy result behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results suggest that DFNA25 stems from a failure in the mechano-transduction
        followed by a change in synaptic transfer.
      explanation: >-
        The authors' claim that this model's structural finding is the disease's starting
        point, which is what makes the model informative for this node.
  - target: Reduced Inner Hair Cell Receptor Potential
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The functional counterpart of the bundle collapse, measured as a reduced summating
      potential in an animal whose cochlear amplifier is intact.
    limitations: >-
      The summating potential is a gross cochlear potential and an indirect index of the
      inner hair cell receptor potential rather than a recording from the cell. It is not
      measured clinically in DFNA25 patients, so there is no human comparison.
    readouts:
    - name: Summating potential
      target: Reduced Inner Hair Cell Receptor Potential
      direction: DECREASED
      interpretation: >-
        A smaller receptor-potential correlate from a mechanically normal input, consistent
        with a transduction rather than an amplification deficit.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The summating potential was reduced, indicating the alteration of inner hair cell
          (IHC) receptor potential.
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The VGLUT3A224V/A224V mouse model opens the way to a deeper understanding and to a
        potential treatment for DFNA25.
      explanation: >-
        The authors' framing of the model as the system for studying this disease.
  - target: Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Oversized ribbons and a faster sustained release rate, appearing later than the
      transduction findings.
    limitations: >-
      The direction is opposite to the null mouse, where ribbons are described as abnormally
      thin and elongated, so the two models disagree about ribbon morphology as well as about
      the order of events. Whether the change is compensatory or injurious is untested, and
      no human ribbon data exist.
    readouts:
    - name: Synaptic ribbon size by super-resolution microscopy
      target: Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
      direction: INCREASED
      interpretation: >-
        Ribbons are larger than wild type in the knock-in animal.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using super-resolution microscopy, we observed oversized synaptic ribbons and
          patch-clamp membrane capacitance measurements showed an increase in the rate of the
          sustained releasable pool exocytosis.
        explanation: >-
          The imaging result behind this readout.
    - name: Sustained releasable pool exocytosis rate
      target: Synaptic Ribbon Enlargement and Altered Sustained Exocytosis
      direction: INCREASED
      interpretation: >-
        Sustained release is faster, not slower. This is the finding that makes the knock-in
        a model of altered rather than failed synaptic transfer.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          patch-clamp membrane capacitance measurements showed an increase in the rate of the
          sustained releasable pool exocytosis
        explanation: >-
          The capacitance measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, IHC ribbon synapses underwent structural and functional modifications at
        later stages.
      explanation: >-
        Supports the model for this node and fixes its position late in the sequence.
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Progressive hearing loss with intact cochlear amplification, which is the human course
      in outline.
    limitations: >-
      Progression is reproduced; the genetics and the audiology are not. The animal is
      homozygous where the patients are heterozygous, and the heterozygote - the matching
      genotype - shows only a small threshold shift with brainstem response amplitudes
      indistinguishable from wild type, which the authors say contrasts with the dominant
      transmission in the human families. The mouse also keeps its distortion-product emissions
      while the patients lose theirs. The authors' own verdict is that the model "might be
      arguable so far as to consider it as a faithful model of DFNA25". The frequency profile of
      the mouse loss is not matched to the human high-frequency-first pattern in any published
      comparison.
    readouts:
    - name: Auditory brainstem response threshold
      target: Progressive High-Frequency Sensorineural Hearing Loss
      direction: INCREASED
      interpretation: >-
        Thresholds rise progressively with age. The direction is INCREASED because the
        readout is a threshold - worse hearing means more sound is required to evoke a
        response.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mutant mice carrying the VGLUT3-p.A211V variant show progressive hearing loss.
        explanation: >-
          The progressive threshold shift behind this readout, stated in the paper's key
          points.
    - name: Distortion-product otoacoustic emissions
      target: Progressive High-Frequency Sensorineural Hearing Loss
      direction: UNCHANGED
      interpretation: >-
        Cochlear amplification is intact while brainstem responses deteriorate. A negative
        result that separates this from an outer-hair-cell hearing loss.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we showed progressive hearing loss with intact cochlear amplification in the
          VGLUT3A224V/A224V mouse
        explanation: >-
          The emissions measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data show that the VGLUT3A224V/A224V mice phenocopy human progressive hearing
        loss.
      explanation: >-
        The authors' own claim that this model matches the human course, which is what
        licenses using it for the clinical phenotype node.
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the mouse model harbouring the VGLUT3-p.A224V variant mimics a progressive hearing loss
        with auditory neuropathy features, but might be arguable so far as to consider it as a
        faithful model of DFNA25
      explanation: >-
        The same authors' qualification of the sentence above, in the discussion rather than the
        abstract. It is recorded as REFUTE against the link's claim of fidelity, and it is why
        this relationship is PARTIALLY_RECAPITULATES.
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, the mild hearing impairment in the VGLUT3+/A224V heterozygotes contrasts with
        the dominant transmission in DFNA25
      explanation: >-
        The zygosity mismatch measured rather than assumed: the genotype that matches a patient
        is only mildly affected in this animal.

diagnosis:

- name: Molecular testing of SLC17A8
  description: >-
    The diagnosis is molecular and there is no audiometric finding that makes it without
    sequencing. SLC17A8 sits on comprehensive hereditary hearing-loss panels; in the reported
    families it has been reached by candidate-gene sequencing after linkage, by targeted
    screening of a dominant cohort, and by whole-exome sequencing. Because penetrance is
    age-dependent, testing an at-risk relative is more informative than audiometry.
  evidence:
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To identify a causative mutation of HL in this family, we performed whole-exome
      sequencing of 4 family members, 3 affected and an unaffected.
    explanation: >-
      The exome route, in a family where linkage was not available.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we performed a genetic analysis of 87 unrelated Korean patients with
      ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean
      population.
    explanation: >-
      The yield to expect from targeted screening: one novel frameshift across 87 unrelated
      dominant probands. SLC17A8 is a rare cause even within dominant nonsyndromic hearing
      loss.

- name: Variant interpretation as a distinct problem in this gene
  description: >-
    Several SLC17A8 variants reported as suspected causes have not been functionally
    confirmed, and a study set up to test two of them found they behave differently from each
    other: c.616dupA reduced both transcript and protein, while c.824C>A left transcript
    levels alone and produced an abnormal protein. Neither result is a segregation study, so
    the practical point is that an SLC17A8 variant list should not be read as a list of
    established mechanisms.
  evidence:
  - reference: PMID:34145196
    reference_title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although several suspected pathogenic mutations of the SLC17a8 gene have been
      identified in humans, few studies have confirmed their pathogenicity.
    explanation: >-
      The interpretation problem stated by the authors as their motivation.
  - reference: PMID:34145196
    reference_title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in
      transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The
      c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this
      mutation did not affect the transcriptional activity of mRNA.
    explanation: >-
      Two alleles in one gene with two different molecular consequences, measured in cell
      culture.

treatments:

- name: Hearing Aids
  therapeutic_modality: DEVICE
  description: >-
    Amplification is the first-line management of a progressive high-frequency sensorineural
    loss and is what DFNA25 patients receive in practice. No DFNA25-specific outcome has been
    published.

    Whether it should be expected to work well depends on which class this disease turns out to
    be in, which is unresolved. If the null mouse's synaptopathy account holds in humans there
    is a mechanistic reason to expect amplification to underperform its audiometric gain, since
    amplification addresses sensitivity and a failure of neural encoding is not a sensitivity
    problem. If instead the absent patient emissions mean outer hair cell function is involved,
    amplification is addressing the right deficit. Nothing here is asserted either way; the
    question is carried by the emissions knowledge gap.
  treatment_term:
    preferred_term: hearing aid fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid

- name: Cochlear Implantation
  therapeutic_modality: DEVICE
  description: >-
    Biologically plausible in this disease for a specific reason rather than a general one:
    in the null mouse the ascending auditory pathway can still be driven by electrical
    stimulation even though it cannot be driven by sound, so an implant that bypasses the
    inner hair cell synapse has an intact target. Whether that generalises to human carriers
    of a missense allele, in whom the synapse is altered rather than absent, is unknown, and
    no DFNA25 implant outcome has been published.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    treatment_effect: BYPASSES
    description: >-
      Direct electrical stimulation of the spiral ganglion substitutes for the defective
      inner hair cell synapse.
    evidence:
    - reference: PMID:18674745
      reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        although auditory brainstem responses could be elicited by electrical stimuli
      explanation: >-
        The preserved electrical responsiveness that an implant would exploit. Model evidence
        for a human intervention, so the claim in the description is plausibility rather than
        efficacy.

- name: AAV-mediated VGLUT3 Gene Replacement
  therapeutic_modality: GENE_THERAPY
  description: >-
    Preclinical only, and preclinical in the null mouse rather than in an animal carrying a
    human allele. Cochlear delivery of AAV1-VGLUT3 normalises brainstem response thresholds
    within two weeks and partially reverses the ribbon synapse changes; delivery to
    five-week-old null mice with an AAV8 vector restored auditory function and recovered
    inner hair cells and stereocilia twenty-seven weeks later.

    Two things stand between this and DFNA25. The disease is dominant, so gene addition may
    not be the right strategy if the human allele acts by anything other than loss of
    function, and the mouse work is gene replacement into a null background. And no
    SLC17A8-specific human trial exists.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Altered VGLUT3 Function in the Inner Hair Cell
    treatment_effect: RESTORES
    description: >-
      Restoring VGLUT3 protein to the inner hair cell addresses the molecular lesion rather
      than its consequences - in an animal that has none of the protein to begin with.
    evidence:
    - reference: PMID:22841313
      reference_title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds
        normalize, along with partial rescue of the startle response.
      explanation: >-
        The functional rescue, in the null mouse.
    - reference: PMID:40841774
      reference_title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Auditory brainstem response (ABR) testing demonstrated restoration of auditory
        function following gene therapy.
      explanation: >-
        Rescue after the neonatal window, which is the version relevant to a postlingual
        human disease.
  evidence:
  - reference: PMID:22841313
    reference_title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings represent a successful restoration of hearing by gene replacement in
      mice, which is a significant advance toward gene therapy of human deafness.
    explanation: >-
      The authors' own framing of how far the result reaches - toward human therapy, not to
      it.

differential_diagnoses:

- name: Presbycusis and noise-induced hearing loss
  description: >-
    The differential that matters, and the reason DFNA25 is probably underdiagnosed. A
    slowly progressive, bilateral, high-frequency sensorineural loss beginning in adult life
    is the audiometric signature of age-related and noise-related hearing loss, which are
    incomparably more common. The founding clinical study says separating them is difficult,
    and the gene paper opens by noting that dominant sensorineural hearing loss as a class
    closely resembles presbycusis. Family history across generations is the discriminator
    available without sequencing.
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is difficult to differentiate delayed-onset high-frequency sensorineural hearing
      loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from
      that due to noise exposure or presbycusis, disorders that may also have a genetic
      component.
    explanation: >-
      The difficulty stated as the study's own conclusion.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a
      phenotype closely resembling presbycusis, the most common sensory defect associated
      with aging in humans.
    explanation: >-
      The same resemblance stated for the dominant class DFNA25 belongs to.

- name: OTOF-related auditory neuropathy (DFNB9)
  description: >-
    The reference genetic auditory synaptopathy, and the disease DFNA25 would sit beside if
    the presynaptic hypothesis is the right one. Otoferlin and VGLUT3 both act presynaptically
    in the inner hair cell and both null mice show preserved emissions with absent neural
    responses. The clinical presentations separate them without difficulty: DFNB9 is
    recessive, prelingual and severe to profound, DFNA25 is dominant, postlingual and
    initially high-frequency. Separation is by inheritance pattern and sequencing, not by
    audiometry.

    The parallel stops at the patients, which is why DFNA25 is not curated as a member of this
    class. DFNB9 is defined clinically by the auditory-neuropathy pattern; in DFNA25 carriers
    otoacoustic emissions are reported absent, so the shared feature is a property of the two
    null mice rather than of the two diseases.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to
      acoustic stimuli, although auditory brainstem responses could be elicited by electrical
      stimuli, and robust otoacoustic emissions were recorded.
    explanation: >-
      The physiological pattern DFNA25's null mouse shares with the OTOF synaptopathies, which
      is what makes DFNB9 the mechanistic differential.

- name: CABP2-related nonsyndromic hearing loss (DFNB93)
  description: >-
    The other synaptic-transmission deafness curated in this knowledge base, and a useful
    contrast rather than a diagnostic difficulty. DFNB93 is recessive, prelingual and
    moderate-to-severe, and its lesion is in the presynaptic calcium channel's regulation
    rather than in vesicle filling. It is included here because the two entries have to agree
    about what is established at the ribbon synapse, and the point is not that DFNA25 lacks
    the human evidence DFNB93 has - it is that the two have the same kind of evidence pointing
    opposite ways. DFNB93 has a human otoacoustic-emission observation showing emissions
    present, which supports its synaptopathy classification. DFNA25 has one showing emissions
    absent, which is why it is not classified that way here.
  evidence:
  - reference: PMID:40927552
    reference_title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2
      variant, indicating preservation of outer hair cell-mediated cochlear amplification.
    explanation: >-
      The DFNB93 half of the contrast, sourced rather than asserted: emissions present in a
      CABP2 family, against emissions absent in DFNA25 carriers. Without this the comparison
      cited only the DFNA25 side.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified SLC17A8, which encodes the vesicular glutamate transporter-3
      (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of
      progressive, high-frequency nonsyndromic deafness.
    explanation: >-
      The dominant, postlingual, high-frequency phenotype that distinguishes DFNA25 from the
      recessive prelingual DFNB93 at the bedside.

discussions:

- discussion_id: mismatch_zygosity_of_the_dfna25_mouse_models
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous SLC17A8 Variant
  - animal_models#Mouse
  prompt: >-
    Does either mouse model DFNA25, when both are homozygous and the heterozygote - the
    genotype a patient actually has - is only mildly affected?
  rationale: >-
    This is not a fidelity quibble; it is a mismatch about the genetic mechanism itself. Both
    published models are homozygous: the Slc17a8 null, which is congenitally and profoundly
    deaf, and the A224V knock-in, which is progressively deaf. The heterozygous knock-in has
    been phenotyped, and it is the genotype that corresponds to a DFNA25 carrier. It shows a
    small threshold shift that reaches statistical significance but leaves brainstem response
    amplitudes indistinguishable from wild-type littermates - which the authors themselves say
    contrasts with the dominant transmission seen in the human families.

    Their explanation is that the stereocilia change is slow relative to a mouse lifespan, so
    a mouse simply does not live long enough to reach the human phenotype from one allele.
    That is plausible and untested. The alternative is that the human allele does something in
    a human inner hair cell that it does not do in a mouse one, in which case the homozygous
    findings are a dose artefact.

    The stake is therapeutic. AAV gene addition rescues the null mouse, and gene addition is
    the obvious translation. But it is the right strategy only if the human allele acts by
    loss of function. If p.A211V is a dominant negative or a toxic gain of function, adding
    wild-type VGLUT3 to a cell that already has a working copy may not help, and an
    allele-selective knockdown would be the rational target instead. Nothing published
    distinguishes those, which is also why the trigger node leaves
    `functional_impact_category` empty. The authors' own summary is that the knock-in "might
    be arguable so far as to consider it as a faithful model of DFNA25".
  proposed_experiments:
  - experiment_id: dfna25_aged_heterozygous_knockin
    name: Lifespan-long auditory phenotyping of heterozygous VGLUT3 A224V mice
    description: >-
      Follow VGLUT3+/A224V mice to the end of their natural lifespan with serial brainstem
      responses, distortion-product emissions and inner hair cell bundle morphology, rather
      than stopping at six months. If the published mild phenotype is a matter of mouse
      lifespan, the deficit should continue to widen against age-matched wild-type
      littermates; if it plateaus, one allele is not sufficient in a mouse.
    would_support:
    - pathophysiology#Heterozygous SLC17A8 Variant
    supporting_outcome:
    - >-
      The heterozygous deficit keeps widening with age and the bundles progressively distort,
      which would make the mouse an under-aged version of the human disease rather than a
      different one, and would license reading the homozygous mechanism across to patients.
    refuting_outcome:
    - >-
      The heterozygous deficit plateaus and the bundles stabilise, which would mean one copy
      of the variant allele is tolerated in a mouse and is not in a human - leaving the
      dominant mechanism of DFNA25 unmodelled by either animal.

- discussion_id: gap_why_patient_emissions_are_absent
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Absent Otoacoustic Emissions
  - mechanistic_hypotheses#presynaptic_glutamate_loading_failure
  prompt: >-
    Are otoacoustic emissions absent in DFNA25 patients because of the disease, or because of a
    lifetime of noise exposure?
  rationale: >-
    This is the question that decides what class DFNA25 belongs to, and it is not a technicality
    about a test.

    Every model says emissions should be preserved. The Slc17a8 null has robust emissions, the
    A224V knock-in has decent distortion-product emissions, and VGLUT3-null data are taken as
    evidence that VGLUT3 has no role in cochlear amplification at all. In the patients, emissions
    are absent. If that is the disease, then outer hair cell function is involved, DFNA25 is not
    an auditory synaptopathy, and the knock-in study's conclusion - that this is a progressive
    hearing loss rather than an auditory neuropathy - stands.

    But DFNA25 is a postlingual disease of adults with a high-frequency audiogram, which is
    exactly the population and exactly the audiometric shape in which acquired noise damage is
    hardest to exclude. The same authors raise noise as the alternative explanation and do not
    test it. If noise is the answer, the underlying disease could still be a synaptopathy whose
    audiological signature has been erased by an acquired overlay - and the entry would be
    filing it in the wrong class on the strength of a confounded measurement.

    Nothing about DFNA25 makes noise exposure implausible; the disease is diagnostically
    confusable with noise-induced hearing loss in the first place, which is recorded as its main
    differential. The authors propose the discriminating experiment themselves.
  proposed_experiments:
  - experiment_id: dfna25_noise_vulnerability_by_allele_dose
    name: Noise vulnerability in mice carrying one or two VGLUT3-p.A224V alleles
    description: >-
      Expose wild-type, heterozygous and homozygous A224V mice to a controlled acoustic
      overexposure and compare distortion-product emission loss and threshold shift against
      unexposed littermates. This is the experiment the knock-in authors name as necessary to
      determine whether acoustic injury accounts for the discrepancy between mouse and patient
      emissions.
    would_support:
    - phenotypes#Absent Otoacoustic Emissions
    supporting_outcome:
    - >-
      Variant-carrying mice lose emissions disproportionately after noise, which would mean the
      absent emissions in patients are an acquired overlay on a genetic synaptopathy, would keep
      DFNA25 inside the auditory neuropathy spectrum, and would make hearing protection a
      disease-modifying intervention rather than general advice.
    refuting_outcome:
    - >-
      Variant-carrying mice are no more noise-vulnerable than wild type, which would leave the
      absent patient emissions as a feature of the disease itself, confirm that outer hair cell
      function is involved, and settle DFNA25 outside the synaptopathies.

- discussion_id: gap_where_the_dfna25_lesion_starts
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#presynaptic_glutamate_loading_failure
  - mechanistic_hypotheses#a211v_mechanotransduction_first
  prompt: >-
    How does a vesicular glutamate transporter variant collapse the inner hair cell stereocilia
    bundle?
  rationale: >-
    The knock-in mouse's primary finding is that inner hair cell bundles fuse and collapse while
    outer hair cell bundles are spared, and no proposed mechanism survives contact with what is
    already known about the protein. VGLUT3 is not present in inner hair cell stereocilia. Losing
    VGLUT3 entirely leaves the transducer working, with an intact hair cell receptor potential.
    So the variant is doing something the null does not.

    The paper's own candidate is a misfolding-and-aggregation model, in which variant protein
    accumulates near the nucleus and jams the traffic that maintains the stereocilia machinery -
    borrowing the mechanism established for DIAPH3 in the auditory neuropathy AUNA1. It then
    argues against its own candidate on two counts: the same point mutation reduces VGLUT3 in
    nerve terminals while leaving the soma unchanged, which is the opposite of somatic
    accumulation, and a structural model shows alanine-to-valine barely perturbs the protein.

    This matters beyond tidiness. The two hypothesis groups in this entry diverge at exactly this
    step, and a gene therapy designed against the synaptic account would not address a
    stereociliary lesion.
  proposed_experiments:
  - experiment_id: dfna25_vglut3_localisation_in_knockin_hair_cells
    name: Subcellular localisation and turnover of VGLUT3-p.A224V in inner hair cells
    description: >-
      Track variant VGLUT3 in knock-in inner hair cells by immunogold electron microscopy and
      pulse-chase, testing directly whether it accumulates in the soma or apical compartment,
      whether proteostasis markers are engaged, and whether the cuticular plate cytoskeleton is
      disturbed before the bundles collapse.
    would_support:
    - mechanistic_hypotheses#a211v_mechanotransduction_first
    supporting_outcome:
    - >-
      Variant protein accumulates with an engaged proteostasis response and cuticular-plate
      disturbance preceding bundle collapse, which would supply the missing mechanism and
      establish the transduction account as the primary one.
    refuting_outcome:
    - >-
      Variant protein localises normally and no proteostasis or cytoskeletal change precedes the
      bundle collapse, which would leave the stereocilia phenotype unexplained and raise the
      possibility that it is a strain or background effect of this particular mouse line rather
      than a consequence of the allele.

- discussion_id: gap_dfna25_allele_class_heterogeneity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#SLC17A8
  prompt: >-
    Do the truncating and splice SLC17A8 alleles cause the same disease as the missense
    founder allele?
  rationale: >-
    The entry treats SLC17A8 as one causative gene because that is how the gene-disease
    relationship is curated, but the alleles do not obviously share a mechanism. p.A211V is a
    conserved missense that leaves vesicular glutamate accumulation intact where it has been
    tested. p.M206Nfs*4 truncates at residue 209 and removes most of the transmembrane
    domains. c.763+1G>T abolishes a splice donor. In vitro work on two further suspected
    alleles found one reduced transcript and protein while the other left transcript alone
    and produced an abnormal protein.

    If the truncating alleles are simple loss of function, then a heterozygous truncating
    carrier is functionally a heterozygous null - and heterozygous null mice hear normally.
    Either mice and humans differ in their tolerance of half-dose VGLUT3, or the truncating
    alleles are doing something other than reducing dosage, or their pathogenicity rests on
    smaller families than the founder allele's. Each of those has a different consequence for
    variant interpretation in a diagnostic laboratory.
  proposed_experiments:
  - experiment_id: dfna25_allele_class_audiogram_comparison
    name: Audiometric comparison of missense against truncating SLC17A8 carriers
    description: >-
      Collect audiograms and ages at onset across all published SLC17A8 heterozygotes and
      compare the founder missense families against the frameshift and splice-donor families,
      testing whether onset, progression rate and audiometric shape differ by allele class.
    would_support:
    - genetic#SLC17A8
    supporting_outcome:
    - >-
      The allele classes are audiometrically indistinguishable, supporting a single gene-level
      disease entity and justifying the current single causative-gene record.
    refuting_outcome:
    - >-
      Truncating carriers are milder, later or less penetrant than missense carriers, which
      would mean DFNA25 as curated conflates two mechanisms and that a truncating SLC17A8
      variant should not be reported with the same prognosis as the founder allele.

notes: >-
  Named entity check. SLC17A8 causes one human disease, and nothing in the knowledge base
  mentioned SLC17A8 or VGLUT3 before this entry. The gene is not a homonym trap in the way
  some are, but two neighbouring confusions were checked and excluded. VGLUT3 has a large
  literature in the central nervous system - striatal cholinergic interneurons, hippocampal
  circuits, tinnitus, optic neuropathy - which is about the same protein in different cells
  and is not this disease; the deep-research run for this entry surfaced one such citation
  and it was not used. And the acronym ABR in the auditory literature is the auditory
  brainstem response, not the ABR gene; the Named Entity Confusion preflight flagged "ABR"
  as a rival gene at 39% of SLC17A8's mention count for exactly that reason, and it is a
  false positive.

  Relationship to Auditory Neuropathy and to DFNB93. This was the substantive question on the
  claim issue, and it has a positive answer rather than a cautious one: DFNA25 is not recorded
  as a subtype of the Auditory Neuropathy entry because the human audiology argues against the
  classification, not merely because it is missing.

  The signature that defines that class is preserved otoacoustic emissions with an absent or
  desynchronised brainstem response. Both mouse models have preserved emissions. The patients
  do not - emissions are reported absent in p.A211V carriers - and the knock-in study draws the
  conclusion explicitly: DFNA25 is more likely a progressive hearing loss in humans than an
  auditory neuropathy. Filing it under Auditory Neuropathy would contradict the only published
  human audiological measurement bearing on the question. The Auditory Neuropathy entry's
  has_subtypes list is populated by entities where the classification rests on a human clinical
  finding (OTOF, DIAPH3, ATP11A, AIFM1, TMEM43), and here the human clinical finding points the
  other way.

  That conclusion is recorded with the qualification its own authors attach to it. Absent
  emissions may instead reflect accumulated noise exposure across a lifetime, in a middle-aged
  cohort whose audiogram is already indistinguishable from noise damage. The alternative is
  curated as a NO_EVIDENCE evidence item and as an open knowledge gap carrying the
  discriminating experiment the authors themselves name - noise vulnerability in mice carrying
  one or two variant alleles.

  This is exactly where DFNB93 differs, and it is how the two entries end up agreeing about the
  ribbon synapse. DFNB93 has a human emissions observation showing emissions PRESENT, which is
  why that entry asserts its synaptopathy classification in its pathophysiology. DFNA25 has a
  human emissions observation showing emissions ABSENT, which is why this entry asserts the
  dissociation for the mouse only and curates the human finding as a phenotype that refutes it.
  Each entry states which species each half of its claim was measured in, and neither borrows
  the other's classification.

  The one human-facing hook to the auditory neuropathy literature that does exist is
  PMID:34145196, which characterises two suspected SLC17A8 alleles under the heading of
  auditory neuropathy. It is cited here for what it measured - two alleles with two different
  molecular consequences in cell culture - and not for the classification in its title, which
  it does not test.

  Why this is a Disease and not a subtype. MONDO:0011568 is bound nowhere in the knowledge
  base and DFNA25 has its own OMIM phenotype entry, its own DFNA locus number and a ClinGen
  Definitive gene-disease assertion of its own. The pathograph is gene-specific down to the
  vesicular transporter and the two competing models of where the lesion starts. There is no
  candidate parent entry that already binds SLC17A8, so no coverage exists to duplicate.

  Evidence grading. Every mechanistic step in this entry is mouse, and every one of those
  items is graded MODEL_ORGANISM. The human anchors are the audiometric phenotype, the
  inheritance pattern, the alleles and the penetrance observations - four papers, three
  families and one screening cohort. Human cochlear tissue is not obtainable, so this
  proportion is a permanent feature of the evidence base rather than an incomplete curation.
  The autaptic-neuron transport experiments and the cell-culture expression work are graded
  IN_VITRO even where they appear in clinical-genetics papers, because evidence_source
  describes the experiment.

  What is deliberately absent. No prevalence record: nine probands worldwide, no population
  study, and any prevalence_class here would be a guess rather than a band. No frequency
  band on any phenotype, for the same reason - there is no denominator that is DFNA25. No
  progression record, because no serial-audiogram data have been published since the 2003
  study of a single pre-gene family and that study reports onset rather than a rate. No
  clinical_trials, because none exist for this gene. No datasets, because a SLC17A8 or VGLUT3
  omics search returns the central-nervous-system literature rather than anything cochlear
  and disease-specific.

  On GeneReviews. There is no SLC17A8 or DFNA25 chapter, so no gene-specific chapter is
  omitted here. The adjacent chapter, PMID:20301607 "Genetic Hearing Loss Overview", is cached
  and is tagged by several sibling nonsyndromic hearing-loss entries, but it does not mention
  SLC17A8, DFNA25 or VGLUT3 anywhere in the cached record - so tagging it would assert a
  coverage relationship the source does not have. It is deliberately left out.

  One provenance caveat on the human otoacoustic-emission finding, which is load-bearing for
  the classification above. It reaches this entry through the discussion of the 2021 knock-in
  paper, which attributes it to the 2003 audiological study of the founding family. That 2003
  abstract does not mention emissions and only the abstract is cached, so the primary
  measurement could not be quoted directly. The entry therefore cites the 2021 paper for what
  it states, and the phenotype carries no frequency band because the underlying denominator is
  a single family described at second hand. A curator with full-text access to the 2003 paper
  should confirm the numbers.

references:
- reference: PMID:18674745
  title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
- reference: PMID:12925340
  title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
- reference: PMID:11115382
  title: "DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24."
- reference: PMID:34783032
  title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
- reference: PMID:18215623
  title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
- reference: PMID:22841313
  title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
- reference: PMID:40841774
  title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
- reference: PMID:41279968
  title: Persistence of vestibular function in the absence of glutamatergic transmission from hair cells.
- reference: PMID:26797701
  title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
- reference: PMID:28647561
  title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
- reference: PMID:40927552
  title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
- reference: PMID:34145196
  title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
- reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
📚

References & Deep Research

References

13
PMID:18674745
Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.
No top-level findings curated for this source.
PMID:12925340
Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
No top-level findings curated for this source.
PMID:11115382
DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24.
No top-level findings curated for this source.
PMID:34783032
VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
No top-level findings curated for this source.
PMID:18215623
Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
No top-level findings curated for this source.
PMID:22841313
Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
No top-level findings curated for this source.
PMID:40841774
Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
No top-level findings curated for this source.
PMID:41279968
Persistence of vestibular function in the absence of glutamatergic transmission from hair cells.
No top-level findings curated for this source.
PMID:26797701
Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
No top-level findings curated for this source.
PMID:28647561
Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
No top-level findings curated for this source.
PMID:40927552
Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry.
No top-level findings curated for this source.
PMID:34145196
The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3.
No top-level findings curated for this source.
CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Named entity check. SLC17A8 causes one human disease, and nothing in the knowledge base mentioned SLC17A8 or VGLUT3 before this entry. The gene is not a homonym trap in the way some are, but two neighbouring confusions were checked and excluded. VGLUT3 has a large literature in the central nervous system - striatal cholinergic interneurons, hippocampal circuits, tinnitus, optic neuropathy - which is about the same protein in different cells and is not this disease; the deep-research run for this entry surfaced one such citation and it was not used. And the acronym ABR in the auditory literature is the auditory brainstem response, not the ABR gene; the Named Entity Confusion preflight flagged "ABR" as a rival gene at 39% of SLC17A8's mention count for exactly that reason, and it is a false positive. Relationship to Auditory Neuropathy and to DFNB93. This was the substantive question on the claim issue, and it has a positive answer rather than a cautious one: DFNA25 is not recorded as a subtype of the Auditory Neuropathy entry because the human audiology argues against the classification, not merely because it is missing. The signature that defines that class is preserved otoacoustic emissions with an absent or desynchronised brainstem response. Both mouse models have preserved emissions. The patients do not - emissions are reported absent in p.A211V carriers - and the knock-in study draws the conclusion explicitly: DFNA25 is more likely a progressive hearing loss in humans than an auditory neuropathy. Filing it under Auditory Neuropathy would contradict the only published human audiological measurement bearing on the question. The Auditory Neuropathy entry's has_subtypes list is populated by entities where the classification rests on a human clinical finding (OTOF, DIAPH3, ATP11A, AIFM1, TMEM43), and here the human clinical finding points the other way. That conclusion is recorded with the qualification its own authors attach to it. Absent emissions may instead reflect accumulated noise exposure across a lifetime, in a middle-aged cohort whose audiogram is already indistinguishable from noise damage. The alternative is curated as a NO_EVIDENCE evidence item and as an open knowledge gap carrying the discriminating experiment the authors themselves name - noise vulnerability in mice carrying one or two variant alleles. This is exactly where DFNB93 differs, and it is how the two entries end up agreeing about the ribbon synapse. DFNB93 has a human emissions observation showing emissions PRESENT, which is why that entry asserts its synaptopathy classification in its pathophysiology. DFNA25 has a human emissions observation showing emissions ABSENT, which is why this entry asserts the dissociation for the mouse only and curates the human finding as a phenotype that refutes it. Each entry states which species each half of its claim was measured in, and neither borrows the other's classification. The one human-facing hook to the auditory neuropathy literature that does exist is PMID:34145196, which characterises two suspected SLC17A8 alleles under the heading of auditory neuropathy. It is cited here for what it measured - two alleles with two different molecular consequences in cell culture - and not for the classification in its title, which it does not test. Why this is a Disease and not a subtype. MONDO:0011568 is bound nowhere in the knowledge base and DFNA25 has its own OMIM phenotype entry, its own DFNA locus number and a ClinGen Definitive gene-disease assertion of its own. The pathograph is gene-specific down to the vesicular transporter and the two competing models of where the lesion starts. There is no candidate parent entry that already binds SLC17A8, so no coverage exists to duplicate. Evidence grading. Every mechanistic step in this entry is mouse, and every one of those items is graded MODEL_ORGANISM. The human anchors are the audiometric phenotype, the inheritance pattern, the alleles and the penetrance observations - four papers, three families and one screening cohort. Human cochlear tissue is not obtainable, so this proportion is a permanent feature of the evidence base rather than an incomplete curation. The autaptic-neuron transport experiments and the cell-culture expression work are graded IN_VITRO even where they appear in clinical-genetics papers, because evidence_source describes the experiment. What is deliberately absent. No prevalence record: nine probands worldwide, no population study, and any prevalence_class here would be a guess rather than a band. No frequency band on any phenotype, for the same reason - there is no denominator that is DFNA25. No progression record, because no serial-audiogram data have been published since the 2003 study of a single pre-gene family and that study reports onset rather than a rate. No clinical_trials, because none exist for this gene. No datasets, because a SLC17A8 or VGLUT3 omics search returns the central-nervous-system literature rather than anything cochlear and disease-specific. On GeneReviews. There is no SLC17A8 or DFNA25 chapter, so no gene-specific chapter is omitted here. The adjacent chapter, PMID:20301607 "Genetic Hearing Loss Overview", is cached and is tagged by several sibling nonsyndromic hearing-loss entries, but it does not mention SLC17A8, DFNA25 or VGLUT3 anywhere in the cached record - so tagging it would assert a coverage relationship the source does not have. It is deliberately left out. One provenance caveat on the human otoacoustic-emission finding, which is load-bearing for the classification above. It reaches this entry through the discussion of the 2021 knock-in paper, which attributes it to the 2003 audiological study of the founding family. That 2003 abstract does not mention emissions and only the abstract is cached, so the primary measurement could not be quoted directly. The entry therefore cites the 2021 paper for what it states, and the phenotype carries no frequency band because the underlying denominator is a single family described at second hand. A curator with full-text access to the 2003 paper should confirm the numbers.

Create: Autosomal Dominant Nonsyndromic Hearing Loss 25 (DFNA25, SLC17A8/VGLUT3) · 2026-09-02T03:47:22Z · View source

New Disease entry for MONDO:0011568 (DFNA25), curated from primary literature plus a falcon deep-research run (preflight WARN, exit 0; the 'ABR' rival-gene warning is the auditory brainstem response acronym, a false positive). entry_type decision: DISEASE. MONDO:0011568 was bound nowhere in kb/, DFNA25 has its own OMIM phenotype entry, DFNA locus number and a ClinGen Definitive gene-disease assertion, and no existing entry binds SLC17A8, so there was no coverage to duplicate. The stub was deleted. Relationship to the two neighbouring entries, which was the substantive question on the issue. DFNA25 is NOT recorded as a subtype of Auditory_Neuropathy. The defining physiological signature of that class - preserved otoacoustic emissions with an abnormal auditory brainstem response - is demonstrated only in the Slc17a8-null and A224V knock-in mice and has never been measured in a DFNA25 patient. The Auditory_Neuropathy has_subtypes list is populated by entities whose classification rests on a human clinical finding (OTOF, DIAPH3, ATP11A, AIFM1, TMEM43). The contrast with Autosomal_Recessive_Nonsyndromic_Hearing_Loss_93 (CABP2) is recorded explicitly in a differential_diagnoses entry and in notes: DFNB93 has a published human emissions observation and therefore states its synaptopathy classification in its pathophysiology, while DFNA25 states the dissociation for the mouse only and carries the human question as an open KNOWLEDGE_GAP. Two mechanistic_hypotheses groups are curated rather than one, because the two mouse models disagree. The Slc17a8 null (presynaptic_glutamate_loading_failure, CANONICAL) shows empty-vesicle release with normal exocytosis. The allele-matched VGLUT3 A224V knock-in (a211v_mechanotransduction_first, EMERGING) reports inner hair cell stereocilia collapse and a reduced summating potential first, with ribbon changes later, and its authors conclude DFNA25 begins in mechanotransduction. A HUMAN_MODEL_MISMATCH discussion records the genetics problem: heterozygous Slc17a8 knockout mice hear normally while heterozygous human p.A211V carriers go deaf, so neither model matches the patients' genotype and the choice between gene addition and allele-selective knockdown is unresolved. functional_impact_category is deliberately left empty on the trigger node for the same reason. Correction made later in the same session, after the entry was first written. The full text of PMID:34783032 was searched for the heterozygous-mouse phenotype and turned up something more important: otoacoustic emissions are reported ABSENT in p.A211V patients - the opposite of both mouse models - and that paper concludes on that basis that DFNA25 is more likely a progressive hearing loss than an auditory neuropathy. The first draft of this entry asserted that patient emissions had never been measured, which was wrong. The correction strengthens the disposition rather than changing it: DFNA25 stays out of the Auditory_Neuropathy has_subtypes list, now for a positive cited reason rather than for absence of evidence. Added an 'Absent Otoacoustic Emissions' phenotype (HP:6000182) carrying the finding, the authors' classification conclusion, and their untested alternative explanation (lifetime noise exposure) as a NO_EVIDENCE item; added a REFUTE evidence item against the preserved-amplification pathophysiology node; and replaced the lesion-site knowledge gap with two better ones - why patient emissions are absent, and how a vesicular transporter variant collapses a stereocilia bundle it is not present in. The same full-text search also replaced an unsourced prose claim. The first draft said heterozygous Slc17a8 KNOCKOUT mice hear normally, which could not be quoted from any cached reference. The citable fact is better: heterozygous A224V KNOCK-IN mice - the genotype that matches a patient - show only mild impairment, which the authors themselves say contrasts with the dominant transmission in the human families. The HUMAN_MODEL_MISMATCH was rewritten around that and its proposed experiment changed, because the experiment the first draft proposed had already been done. Process note worth recording: the correction took two commits because the first edit script aborted partway on a failed string match and wrote nothing, so two passages - the notes paragraph and the DFNB93 differential - kept the pre-correction wording while the rest of the entry had moved. Grepping the file for the stale phrase is what caught it. After any script-driven edit, confirm the change landed rather than assuming the script ran to completion. Review round (ai4c-reviewer). The first run approved at 45a4e221bc; a re-run of the same check on the same commit returned CHANGES_REQUESTED, so the later verdict was treated as live rather than stale after confirming both reviews carry the head SHA. One blocking item, verified before acting and correct: Cochlear Implantation bound only NCIT:C15329 Surgical Procedure while Hearing Aids in the same file attached the NCIT:C16830 -> NCIT:C183182 device qualifier pair, so the file was inconsistent with itself and NCIT:C157820 was unreachable from the entry. CLAUDE.md names cochlear implantation as the worked case for exactly this pattern and fifteen entries already follow it. Added the qualifier pair; just check-qualifier-terms-online passes (325 labels matched, 97 resolved online). Two suggestions taken. The DFNB93 differential argued a contrast whose DFNB93 half - emissions present - was unsourced in this file; it now cites PMID:40927552 for the Italian family observation, so both halves of the comparison carry evidence. And the notes now close the GeneReviews loop: there is no SLC17A8 or DFNA25 chapter, and the adjacent Genetic Hearing Loss Overview (PMID:20301607) is deliberately not tagged because the cached record does not mention SLC17A8, DFNA25 or VGLUT3 - tagging it would assert a coverage relationship the source does not have. Two suggestions declined with reasons on the PR: noise exposure stays out of environmental: because the entry treats it as an open question in a knowledge gap rather than an asserted exposure, and adding it would assert what the gap exists to ask; and the DR-surfaced supportive-care items are neither DFNA25-specific nor snippet-supportable. Process note from this round: an edit anchored on '- reference: PMID:34145196' matched inside an indented evidence block before reaching the top-level references: list, producing invalid YAML. Caught by running the validator rather than trusting the script's success. Anchor on a line-start pattern and assert the match count. Deliberately absent: no prevalence (nine probands worldwide), no phenotype frequency bands (no denominator that is DFNA25), no progression, no clinical_trials, no datasets. Ontology note: the deep-research report proposed HP:0012715 as 'Bilateral hearing impairment' (it is Profound hearing impairment) and HP:0002066 as 'Hearing impairment' (it is Gait ataxia). Both were caught by resolving through OLS and were not used. Validation: just validate exit 0 (65/65 snippets verified), just validate-terms exit 0, check-duplicate-keys / check-entity-refs / check-causal-targets all exit 0.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 35 citations 2026-09-01T20:20:31.017754

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Dominant Nonsyndromic Hearing Loss 25
  • MONDO ID: MONDO:0011568 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autosomal Dominant Nonsyndromic Hearing Loss 25 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Autosomal Dominant Nonsyndromic Hearing Loss 25 (DFNA25)

Executive summary

Autosomal dominant nonsyndromic hearing loss 25 (DFNA25) is a very rare, progressive, predominantly high-frequency sensorineural hearing loss caused by heterozygous pathogenic variants in SLC17A8, which encodes vesicular glutamate transporter 3 (VGLUT3/VGluT3). VGLUT3 loads glutamate into synaptic vesicles of cochlear inner hair cells (IHCs), enabling transmission from IHC ribbon synapses to type I spiral-ganglion neurons. Human evidence remains limited to a small number of families, so disease-specific prevalence, quantitative penetrance, progression rates, and quality-of-life statistics are not established. The strongest therapeutic evidence is preclinical: AAV-mediated VGLUT3 replacement has restored hearing in neonatal and adult Slc17a8-null mice, but no DFNA25-specific human gene-therapy trial or approved disease-modifying drug was identified.

The following table provides an ontology-ready synopsis.

domain established finding evidence type suggested ontology terms/IDs key evidence
disease identifier Autosomal Dominant Nonsyndromic Hearing Loss 25 (DFNA25) is a Mendelian deafness entity linked to SLC17A8 Human pedigree/genetic discovery MONDO:0011568; OMIM 605583 DFNA25 described as an "autosomal-dominant form of progressive, high-frequency nonsyndromic deafness" caused by SLC17A8 mutation (ruel2008impairmentofslc17a8 pages 1-2)
causal gene/protein SLC17A8 encodes vesicular glutamate transporter 3 (VGLUT3) Human, mouse, review SLC17A8; VGLUT3; OMIM 607557 VGLUT3 loads glutamate into inner hair cell synaptic vesicles before release to auditory nerve terminals (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2)
synonyms DFNA25; deafness, autosomal dominant 25; SLC17A8-related autosomal dominant nonsyndromic hearing loss Aggregated disease/gene nomenclature with primary literature support OMIM 605583; SLC17A8-related hearing loss Primary papers and reviews use DFNA25 / deafness, autosomal dominant 25 terminology (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2)
pathogenic variants Reported disease-associated variants include c.632C>T (p.A211V), p.M206Nfs*4, and c.763+1G>T Human genetic studies HGVS nomenclature where known; ACMG classification not uniformly published p.A211V segregated in two unrelated families and was absent in 267 controls; p.M206Nfs*4 absent in 100 controls; c.763+1G>T co-segregated in a 3-generation Korean family (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2, ryu2017identificationofa pages 1-6)
inheritance Inheritance is autosomal dominant Human pedigree HP:0000006 Autosomal dominant inheritance Multiple families showed autosomal-dominant segregation (ruel2008impairmentofslc17a8 pages 1-2, ryu2017identificationofa pages 1-6)
core phenotype Progressive high-frequency sensorineural hearing loss, nonsyndromic Human clinical HP:0000407 Sensorineural hearing impairment; HP:0002066 Hearing impairment; high-frequency qualifier if used in HPO mapping Human families had delayed/progressive high-frequency SNHL without syndromic features (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2)
onset/natural history Typically delayed/late onset with age-related penetrance increase and progression over time Human pedigree/clinical HPO terms for progressive hearing impairment; adult/late onset descriptors as appropriate DFNA phenotypes are described as delayed-onset and progressive; DFNA25 specifically showed age-related penetrance increase (ruel2008impairmentofslc17a8 pages 1-2, ruel2008impairmentofslc17a8 pages 13-14, ryu2016screeningofthe pages 1-2)
syndromic status No consistent extra-auditory syndromic findings established Human clinical HP:0000007 Autosomal dominant inheritance; nonsyndromic descriptor Korean family report noted hearing loss was non-syndromic with no accompanying symptoms (ryu2017identificationofa pages 1-6)
primary anatomy Primary site is the cochlea, especially the organ of Corti inner hair cell synapse Human-mechanistic inference supported by mouse and expression data UBERON: cochlea; organ of Corti; inner hair cell VGLUT3 is selectively expressed in cochlear inner hair cells and mediates afferent transmission (ryu2016screeningofthe pages 1-2, ruel2008impairmentofslc17a8 pages 1-2)
affected cells Inner hair cells are primary; type I spiral ganglion neuron afferents are secondarily affected Mouse physiology/morphology with human disease relevance CL: inner hair cell; spiral ganglion neuron Slc17a8-null mice lacked acoustic auditory-nerve responses and later showed decline in afferent synapses and spiral ganglion neurons (ruel2008impairmentofslc17a8 pages 1-2, ruel2008impairmentofslc17a8 pages 13-14)
subcellular localization VGLUT3 localizes to synaptic vesicle-like glutamatergic organelles/ribbon-synapse trafficking compartments in IHCs Proteomics, prior functional work GO cellular component: synaptic vesicle; presynaptic active zone; synaptic ribbon 2024 proteomics isolated "VGluT3-containing membrane vesicles" from IHCs and profiled ribbon-synapse trafficking machinery (cepeda2024proteomicanalysisreveals pages 1-3)
mechanism Impaired vesicular glutamate loading/release at the IHC ribbon synapse leads to failure of auditory nerve activation; downstream synapse and neuron loss can follow Human genetic inference plus mouse functional demonstration GO: glutamate transport; chemical synaptic transmission; synaptic vesicle cycle Null mice had absent acoustically evoked ABRs but preserved electrically evoked ABRs and otoacoustic emissions, supporting a synaptic glutamate-release defect rather than OHC failure (ruel2008impairmentofslc17a8 pages 1-2, ruel2008impairmentofslc17a8 pages 13-14)
variant-specific mechanism The human p.A211V allele is modeled by mouse p.A224V and is associated with IHC stereocilia collapse, reduced summating potential, and oversized synaptic ribbons Mouse knock-in model of human allele GO: mechanotransduction; synaptic transmission; hair bundle organization Knock-in mice showed progressive hearing loss with intact cochlear amplification, IHC bundle collapse, and altered ribbon exocytosis, suggesting mechanotransduction failure followed by altered synaptic transfer (joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
diagnostic testing Diagnosis relies on audiologic evaluation plus molecular testing (single gene, deafness panel, WES/WGS depending context) Clinical genetics practice supported by gene-specific reports SLC17A8 sequencing; hereditary hearing loss panel SLC17A8 mutations were identified by candidate-gene sequencing and by whole-exome sequencing in affected families (ryu2016screeningofthe pages 1-2, ryu2017identificationofa pages 1-6)
electrophysiology ABR is abnormal from failed acoustic neural transmission; OAE/DPOAE may remain preserved when OHC function is intact Mouse functional evidence; clinically relevant inference ABR; otoacoustic emissions Slc17a8-null mice lacked auditory-nerve responses to sound yet retained robust otoacoustic emissions; p.A224V model had progressive ABR loss with intact DPOAEs (ruel2008impairmentofslc17a8 pages 1-2, joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
treatment status No DFNA25-specific approved molecular therapy identified; current real-world care is supportive/rehabilitative (hearing aids, cochlear implantation as indicated) Review plus mechanistic/animal evidence NCIT: Hearing Aid; Cochlear Implantation Reviews note hearing aids and cochlear implants remain standard care for hereditary deafness; SLC17A8-specific therapy remains preclinical (duhon2024genetherapyadvancements pages 4-5, zhang2024aav‐mediatedgenetherapy pages 3-4)
cochlear implant implication Because neural responses to electrical stimulation are preserved in Slc17a8-null mice, cochlear implantation is considered biologically plausible Mouse translational inference NCIT: Cochlear Implantation Electrically evoked ABRs were preserved in null mice, suggesting bypass of the defective IHC synapse may help (ruel2008impairmentofslc17a8 pages 13-14)
gene therapy/preclinical AAV1-VGLUT3 cochlear delivery rescued hearing in Vglut3 knockout mice; early postnatal RWM delivery achieved 100% normal ABR threshold recovery in one series Mouse preclinical interventional AAV gene replacement; VGLUT3 gene augmentation Akil 2012 reported normalized ABR thresholds within 2 weeks; P1-P3 RWM delivery rescued 19/19 mice and some maintained hearing long term (akil2012restorationofhearing pages 1-2, akil2012restorationofhearing pages 6-8)
mature-cochlea translational development 2023 mature-mouse CSF/cisterna magna delivery of AAV-PHP.B-CBA-VGLUT3-WPRE reportedly restored hearing in SLC17A8-/- mice except at 40 kHz Review summarizing preclinical primary study AAV-PHP.B; cisterna magna delivery 2024 review summarizes mature-mouse rescue at dose 2.27 × 10^11 vg with limited off-target expression reported (duhon2024genetherapyadvancements pages 11-12)
human trials status No human interventional trial specific to SLC17A8/DFNA25 was identified in the tool-based search Trial search / evidence gap ClinicalTrials.gov status: none identified for this gene-disease pair Recent reviews discuss human OTOF trials, not SLC17A8-specific trials; trial search returned no relevant SLC17A8 intervention (zhang2024aav‐mediatedgenetherapy pages 3-4, duhon2024genetherapyadvancements pages 4-5)
model organisms Key models are Slc17a8 knockout mice and VGLUT3A224V/A224V knock-in mice modeling human p.A211V Mouse in vivo models MGI/IMSR resources if needed; Slc17a8 mouse models Knockout demonstrates synaptic glutamate-release failure; knock-in models progressive/mechanosensory and synaptic pathology (ruel2008impairmentofslc17a8 pages 1-2, joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
comparative conservation The affected alanine residue is conserved across species and among human VGLUT paralogs Human/mouse comparative sequence evidence conserved residue annotation Conservation of A211 supported pathogenic relevance of p.A211V (ruel2008impairmentofslc17a8 pages 1-2)
epidemiology Disease-specific prevalence, incidence, sex ratio, and carrier frequency are not established in the retrieved DFNA25-specific literature Explicit data gap not available Available papers are family-based discovery/screening studies rather than population epidemiology (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2)
penetrance/expressivity Penetrance appears age-dependent and expressivity likely variable, but robust quantitative estimates are lacking Human pedigree with data gap age-dependent penetrance descriptor Human paper notes age-related penetrance increase; no precise percent penetrance estimate retrieved (ruel2008impairmentofslc17a8 pages 13-14)
environmental modifiers No DFNA25-specific environmental risk or protective modifiers were established in retrieved primary disease papers Explicit data gap not available Reviews discuss generic contributors to hearing loss (noise, aging), but not validated DFNA25-specific gene-environment interactions (ruel2008impairmentofslc17a8 pages 1-2, bottom2024defectsinhair pages 1-2)
QoL/prognosis gap No DFNA25-specific quality-of-life or life-expectancy studies were identified; morbidity is expected to derive mainly from chronic progressive hearing impairment Explicit data gap with general clinical inference hearing-disability QoL instruments if studied in future Family reports focus on hearing phenotype/genetics, not QoL or survival outcomes (ruel2008impairmentofslc17a8 pages 1-2, ryu2016screeningofthe pages 1-2)

Table: This table condenses the most actionable, ontology-ready facts for DFNA25/SLC17A8-related hearing loss, including core identifiers, phenotype, mechanism, models, and treatment status. It also flags major evidence gaps where disease-specific epidemiology, modifiers, and outcomes are not yet established.

1. Disease information

Definition and identifiers

DFNA25 is an inherited, nonsyndromic cochlear disorder characterized by progressive high-frequency sensorineural hearing impairment. The landmark report described it as an “autosomal-dominant form of progressive, high-frequency nonsyndromic deafness.” (ruel2008impairmentofslc17a8 pages 1-2)

  • Preferred name: Autosomal dominant nonsyndromic hearing loss 25
  • Synonyms: DFNA25; deafness, autosomal dominant 25; SLC17A8-related autosomal dominant nonsyndromic hearing loss
  • MONDO: MONDO:0011568
  • OMIM phenotype: 605583, DFNA25
  • Causal gene/protein: SLC17A8, VGLUT3; OMIM 607557
  • Locus: chromosome 12q21–q24.5 in the original linkage interval
  • ICD-10-CM: no DFNA25-specific code; generally coded under H90.3 (bilateral sensorineural hearing loss) or another audiometrically appropriate H90 category
  • ICD-11/MeSH: no uniquely specific DFNA25 entry was established in the retrieved literature; broader hereditary/sensorineural hearing-loss concepts apply.

The foundational human evidence came from pedigrees, clinical audiometry, linkage analysis, and germline DNA sequencing—not individual EHR-derived records. The broader identifiers and nomenclature are aggregated disease-level annotations.

The discovery article was published 8 August 2008 in the American Journal of Human Genetics, DOI 10.1016/j.ajhg.2008.07.008, PMID 18674745. Its abstract states: “We have identified SLC17A8…as the gene responsible for DFNA25.” (ruel2008impairmentofslc17a8 pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is a heterozygous germline SLC17A8 variant affecting VGLUT3. The best-established allele, NM_139319.2:c.632C>T, p.(Ala211Val), segregated with hearing loss in two nominally unrelated families and was absent from 267 controls; linkage-disequilibrium analysis suggested distant common ancestry. The alanine is conserved across species and all three human VGLUT paralogs. (ruel2008impairmentofslc17a8 pages 1-2)

Additional reported alleles include:

  • p.(Met206AsnfsTer4): heterozygous frameshift predicted to terminate at residue 209 and remove transmembrane domains 5–12. It was found while screening 87 unrelated Korean patients with ADNSHL and was absent from 100 normal-hearing controls. The original authors described it as “likely” pathogenic; current ClinVar assertions should be checked at ingestion time rather than inferred from that wording. Publication: January 2016; DOI 10.1186/s12881-016-0269-3. (ryu2016screeningofthe pages 1-2)
  • c.763+1G>T: canonical splice-donor variant identified by WES in a three-generation Korean family. It was present in three affected relatives, absent from the tested unaffected relative and 100 normal-hearing controls, and was reported as probably pathogenic. Publication: September 2017; DOI 10.1016/j.gene.2017.06.040. (ryu2017identificationofa pages 23-25, ryu2017identificationofa pages 1-6)

These are germline, not somatic, variants. Population allele frequencies were not supplied in the retrieved primary evidence; contemporary gnomAD frequencies and transcript-normalized HGVS should be obtained directly before clinical interpretation.

Genetic mechanism and modifiers

Simple haploinsufficiency is unlikely to explain every DFNA25 allele: heterozygous Slc17a8 knockout mice have normal hearing and anatomy, whereas humans heterozygous for p.A211V develop age-dependent disease. This supports an allele-specific dominant-negative or toxic gain-of-function mechanism for p.A211V, although the precise molecular interaction remains unresolved. Truncating and splice variants may act differently, and pathogenicity should therefore be evaluated allele by allele. (ruel2008impairmentofslc17a8 pages 13-14)

No replicated modifier gene, protective SLC17A8 allele, epigenetic modifier, founder frequency, or germline-mosaicism estimate has been established. Family history is the major ascertainable risk factor; each child of a heterozygous affected person has a 50% transmission probability, although age-dependent penetrance complicates phenotype-based testing.

Environment and gene–environment interaction

Noise, aging, and ototoxic agents are established general causes or accelerants of cochlear synaptopathy, but no study has quantified a DFNA25-specific interaction. Recent work notes that genetic defects, loud noise, ototoxic drugs, and aging can all compromise IHC synaptic sound encoding. Consequently, noise and ototoxin avoidance is biologically reasonable but not proven to alter DFNA25 natural history. (bottom2024defectsinhair pages 1-2, cepeda2024proteomicanalysisreveals pages 1-3)

No specific diet, exercise program, supplement, vaccine, or medication has been demonstrated to prevent genetically initiated DFNA25.

3. Phenotypes

Core phenotype

The principal phenotype is bilateral, nonsyndromic, sensorineural hearing impairment, initially most prominent at high frequencies and progressive with age. Onset is generally delayed rather than congenital in the original p.A211V families, and penetrance rises with age. Severity and onset vary among carriers; robust percentages and annual threshold-shift estimates are unavailable. (ruel2008impairmentofslc17a8 pages 1-2, ruel2008impairmentofslc17a8 pages 13-14)

Suggested annotations are:

  • Sensorineural hearing impairment — HP:0000407
  • High-frequency hearing impairment — use the current HPO high-frequency term at database ingestion
  • Progressive hearing impairment — HP:0001730
  • Bilateral hearing impairment — HP:0012715
  • Autosomal dominant inheritance — HP:0000006
  • Adult/late onset — apply only when documented for the individual, because onset is variable

Preserved otoacoustic emissions and synaptic/auditory-neuropathy physiology are strongly demonstrated in mice, but should not automatically be entered as universal human phenotypes. In the null model, robust OAEs coexisted with absent sound-evoked auditory-nerve responses, localizing dysfunction downstream of outer-hair-cell amplification. (ruel2008impairmentofslc17a8 pages 1-2)

No consistent vestibular, visual, neurologic, renal, endocrine, craniofacial, or behavioral abnormality has been reported; a Korean pedigree specifically had no accompanying symptoms. (ryu2017identificationofa pages 1-6)

Functional and quality-of-life consequences

Disease-specific EQ-5D, SF-36, PROMIS, speech-recognition, educational, or employment data are unavailable. By clinical inference, progressive high-frequency loss can impair speech understanding—particularly consonants and speech in noise—communication, education, work, and social participation. These generic consequences should not be represented as measured DFNA25 outcomes.

4. Genetic and molecular information

SLC17A8 encodes a 589-amino-acid, predicted 12-transmembrane-domain major-facilitator-superfamily transporter. In cochlear IHCs, VGLUT3 packages glutamate into vesicles for release at ribbon synapses. (ryu2016screeningofthe pages 1-2)

Relevant molecular annotations include:

  • GO biological process: glutamate transmembrane transport; synaptic-vesicle loading; chemical synaptic transmission; synaptic-vesicle cycle; sensory perception of sound.
  • GO molecular function: vesicular glutamate transmembrane transporter activity.
  • GO cellular component: synaptic vesicle membrane; glutamatergic synapse; presynaptic active zone; ribbon synapse.
  • CHEBI: L-glutamate (CHEBI:29985).

No large recurrent deletion, inversion, translocation, aneuploidy, DNA-methylation signature, or disease-specific chromatin abnormality is established. Likewise, no validated prognostic transcriptomic, circulating, metabolomic, lipidomic, or epigenomic biomarker exists.

5. Environmental information

DFNA25 is not infectious, toxic, occupational, or lifestyle-caused. Environmental exposures may add independent cochlear injury to the inherited defect. Avoidable generic hazards include excessive sound, aminoglycosides when alternatives exist, cisplatin, and other recognized ototoxins. There is no evidence that smoking, alcohol, diet, exercise, radiation, pollution, or a pathogen specifically changes SLC17A8 penetrance.

A rat salicylate model found increased IHC VGLUT3 expression and tinnitus without a significant hearing-threshold difference, but this is acquired-toxicity evidence and does not establish salicylate as a DFNA25 modifier.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous pathogenic SLC17A8 lesion leads to altered amount, structure, trafficking, or function of VGLUT3 in cochlear IHCs.
  2. Altered VGLUT3 leads to defective glutamate accumulation in IHC synaptic vesicles; this is directly demonstrated for complete loss of VGLUT3 and inferred, with allele-specific complexities, for human dominant variants. (ruel2008impairmentofslc17a8 pages 12-13, ruel2008impairmentofslc17a8 pages 1-2)
  3. In the loss-of-function branch, empty or inadequately loaded vesicles can still undergo Ca²⁺-triggered exocytosis, but insufficient glutamate release results in failure to activate type I spiral-ganglion afferents. Vesicle turnover and exocytotic kinetics were initially preserved in null IHCs. (ruel2008impairmentofslc17a8 pages 12-13)
  4. In the p.A211V branch, the modeled mouse allele p.A224V leads to IHC stereociliary-bundle collapse and reduced receptor potential, followed by oversized ribbons and altered sustained exocytosis; these findings suggest primary mechano-transduction failure plus later synaptic dysfunction rather than pure transporter insufficiency. (joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
  5. Failed or distorted IHC-to-afferent signaling results in reduced auditory-nerve activity and elevated/absent acoustically evoked ABRs, while outer-hair-cell cochlear amplification may remain intact. (ruel2008impairmentofslc17a8 pages 1-2, joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
  6. Chronic loss of afferent activity leads to secondary decline of IHC afferent synapses, spiral-ganglion neurons, and lateral efferent endings; altered trophic support and activity-dependent circuit maturation are plausible mediators. (ruel2008impairmentofslc17a8 pages 12-13, ruel2008impairmentofslc17a8 pages 13-14)
  7. Tonotopically unequal vulnerability, not yet fully explained, results in the characteristic progressive high-frequency sensorineural hearing phenotype.

The principal upstream lesion is vesicular transporter dysfunction; mechano-transduction and ribbon abnormalities may be allele-specific parallel or downstream processes. Secondary neural/circuit degeneration is downstream. No primary immune, fibrotic, ischemic, endocrine, or metabolic mechanism has been demonstrated.

Suggested cell terms are inner hair cell, type I spiral-ganglion neuron, and secondarily lateral olivocochlear efferent neuron. Suggested anatomical terms are cochlea, organ of Corti, spiral ganglion, and IHC ribbon synapse. Exact CL/UBERON identifiers should be ontology-validated during curation.

Recent molecular profiling

A 2024 study used subcellular fractionation, anti-VGluT3 immunoisolation, label-free LC–MS, and imaging to generate the first broad proteomic inventory of native IHC trafficking organelles. It identified an age-dependent, mixed synaptic-vesicle/endosomal signature and enrichment after hearing onset of VAMP7, syntaxins 7/8/12–13, SCAMP1, V-ATPase, SV2, and PKCα. This profiles normal VGLUT3-positive organelles rather than DFNA25 patient tissue, but supplies an authoritative molecular framework for studying variant effects. Publication: February 2024; DOI 10.1016/j.mcpro.2023.100704. (cepeda2024proteomicanalysisreveals pages 1-3)

No DFNA25 patient-derived single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, organoid, iPSC, or CRISPR-screen dataset was identified.

7. Anatomical structures affected

  • Primary organ/system: inner ear/cochlea; auditory sensory system.
  • Primary tissue: sensory epithelium of the organ of Corti.
  • Primary cell: IHC, especially its apical stereociliary bundle for p.A211V-like disease and basolateral ribbon-synapse vesicular compartment for VGLUT3 function.
  • Secondary cells: IHC-afferent terminals and type I spiral-ganglion neurons; lateral efferent endings decline in null mice.
  • Relatively preserved structure: OHCs and cochlear amplification in the principal mouse models, reflected by robust OAE/DPOAE measurements. (ruel2008impairmentofslc17a8 pages 1-2, joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
  • Laterality: human disease is understood as bilateral; asymmetry is not a defining feature.

VGLUT3 is also expressed in selected central neurons, but DFNA25 is clinically nonsyndromic and no reproducible central-neurologic phenotype is established.

8. Temporal development

The human course is chronic and lifelong: high-frequency thresholds typically deteriorate progressively, with age-dependent clinical penetrance. There are no validated early/intermediate/end-stage definitions, median onset age, dB/year trajectory, spontaneous remissions, or episodic pattern. (ruel2008impairmentofslc17a8 pages 13-14)

The mouse evidence suggests two potentially important intervention windows. First, restoring neurotransmission before secondary spiral-ganglion loss should be advantageous. Second, treatment remains possible after auditory maturation: adult-mouse rescue has been reported, although delivery and neural preservation become more difficult. Neonatal mice are unusually permissive to AAV and do not directly model the fully developed human neonatal cochlea. (duhon2024genetherapyadvancements pages 11-12, duhon2024genetherapyadvancements pages 4-5)

9. Inheritance and population

Inheritance is autosomal dominant. Both sexes are expected to be affected equally and male-to-male transmission is possible. Penetrance appears age-dependent; no defensible percentage is available. Expressivity is variable, while anticipation has not been shown. Consanguinity is not etiologically important for this dominant condition.

A distant founder relationship was suggested for the two p.A211V families of Czech/German ancestry, but there is no population-wide founder-frequency estimate. Korean frameshift and splice variants demonstrate that DFNA25 is not confined to European ancestry. (ruel2008impairmentofslc17a8 pages 1-2, ryu2017identificationofa pages 1-6)

Disease-specific prevalence, incidence, carrier frequency, geographic distribution, sex ratio, and age distribution are unknown. The Korean screening study found one proposed frameshift allele among 87 unrelated ADNSHL probands, but this selected sample cannot be converted into population prevalence. For context only, the paper reported that roughly 70% of hereditary SNHL is nonsyndromic and that 10–20% of nonsyndromic cases follow dominant inheritance; these are not DFNA25-specific statistics. (ryu2016screeningofthe pages 1-2)

10. Diagnostics

Clinical evaluation

Recommended assessment includes otologic examination, family history over at least three generations, pure-tone air/bone audiometry, speech audiometry including speech-in-noise where available, tympanometry, and serial threshold monitoring. OAEs and ABR can help localize cochlear amplification versus IHC-synaptic/neural transmission, but no DFNA25-specific diagnostic cut-off exists.

Imaging is usually unnecessary in a classic bilateral hereditary presentation but may be appropriate for asymmetry, vestibular symptoms, cochlear-implant planning, or another suspected structural cause. Routine blood chemistry, biopsy, EEG, EMG, or metabolic testing does not diagnose DFNA25.

Genetic testing strategy

  1. Use a comprehensive hereditary-hearing-loss panel containing SLC17A8, with copy-number calling where technically validated.
  2. Use exome or genome sequencing when a panel is negative, the phenotype is atypical, or broader reanalysis is desirable. WES identified c.763+1G>T in the Korean pedigree. (ryu2017identificationofa pages 1-6)
  3. Confirm reportable variants by an orthogonal method as appropriate, evaluate segregation, and apply current ACMG/AMP and hearing-loss specifications.
  4. For a splice variant, RNA analysis can provide useful functional confirmation when an informative tissue or minigene assay is feasible.
  5. Once a familial pathogenic variant is established, use targeted testing for relatives, prenatal diagnosis, or preimplantation genetic testing.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line tests for isolated, sequence-variant-mediated DFNA25 unless another diagnosis is suspected.

Differential diagnosis

The differential includes other progressive dominant nonsyndromic hearing losses—such as KCNQ4/DFNA2A, TECTA/DFNA8/12, WFS1/DFNA6/14/38, ACTG1/DFNA20/26, POU4F3/DFNA15, TMC1/DFNA36, and COCH/DFNA9—plus age/noise-related loss, ototoxicity, congenital infection, and structural disease. Vestibular dysfunction strongly suggests alternatives such as COCH-related disease. Molecular diagnosis is essential because audiograms overlap.

Newborn hearing screening can miss delayed-onset DFNA25. Children carrying a familial variant require scheduled audiologic surveillance even after a normal newborn screen.

11. Outcome and prognosis

DFNA25 is not known to reduce survival or life expectancy, and no disease-specific mortality is reported. Morbidity is auditory: progressive communication disability may eventually require amplification or implantation. Spontaneous biological recovery is not expected, although functional rehabilitation is often substantial.

Baseline severity, age of onset, serial threshold slope, speech recognition, and preservation of spiral-ganglion function are clinically relevant prognostic features. No molecular biomarker predicts progression beyond the familial variant and family-specific natural history. No five- or ten-year survival statistic is applicable.

12. Treatment and current implementation

Current care

There is no approved DFNA25-specific drug, RNA therapy, gene therapy, or pharmacogenomic guideline. Current management is individualized:

  • Hearing aids for aidable mild-to-severe loss—suggested NCIT annotation: Hearing Aid.
  • Assistive listening/remote-microphone systems, captioning, communication accommodations, and auditory rehabilitation.
  • Speech-language and educational support, especially for childhood onset.
  • Cochlear implantation for severe-to-profound loss or poor aided speech recognition—suggested NCIT annotation: Cochlear Implantation.

Cochlear implantation is mechanistically plausible because electrically evoked ABRs remained present in Slc17a8-null mice even when acoustic responses were absent, indicating that electrical stimulation can bypass the defective IHC synapse. This is translational inference, not a DFNA25-specific clinical outcome series. (ruel2008impairmentofslc17a8 pages 13-14)

Experimental gene replacement

In 2012, cochlear AAV1-VGLUT3 delivery to knockout mice produced IHC-selective protein expression and normalized ABR thresholds within two weeks. At postnatal days 1–3, round-window delivery rescued normal ABR thresholds in 19/19 mice; five followed for nine months retained normal thresholds. A 1-µL dose at 2.3×10¹³ vg/mL labeled 100% of IHCs, whereas 0.6 µL labeled about 40%; even partial IHC transduction could restore near-normal thresholds. Some rescued animals retained normal thresholds for up to 1.5 years, although neural counts and response amplitudes did not fully normalize. Publication: 26 July 2012, Neuron; DOI 10.1016/j.neuron.2012.05.019, PMID 22794260. (akil2012restorationofhearing pages 1-2, akil2012restorationofhearing pages 6-8, akil2012restorationofhearing pages 9-10)

A 2023 study summarized in a 2024 review delivered AAV-PHP.B-CBA-VGLUT3-WPRE into the cisterna magna of mice aged P28–P105. A dose of 2.27×10¹¹ vg reportedly restored hearing across tested frequencies except 40 kHz. Minimal brain expression and no liver expression were reported, but spinal-cord, dorsal-root-ganglion, and liver-vector-genome analyses were incomplete. The review appropriately highlights dorsal-root-ganglion toxicity seen in 83% of 213 nonhuman primates across other intracisternal AAV studies, making safety and species-specific tropism major translational barriers. (duhon2024genetherapyadvancements pages 11-12)

For dominant p.A211V-like disease, simple addition of wild-type SLC17A8 may not suppress a dominant-negative/toxic mutant allele. Mutation-agnostic silencing plus replacement, allele-specific silencing, or editing may ultimately be required; none has yet been validated clinically for DFNA25.

Recent expert reviews conclude that VGLUT3 replacement is among the most successful preclinical hearing-loss programs, sometimes restoring wild-type ABR thresholds, but emphasize poorer adult transduction and incomplete ABR wave-I/neural rescue. One review contrasts approximately 100% IHC/~75% spiral-ganglion-neuron transduction in neonatal mice with 100% IHC but <20% SGN transduction in adults. (duhon2024genetherapyadvancements pages 4-5)

A search of ClinicalTrials.gov found no SLC17A8/DFNA25-specific human interventional trial. Human hereditary-deafness gene-therapy trials described in the 2024 literature concern chiefly OTOF/DFNB9, not DFNA25. (zhang2024aav‐mediatedgenetherapy pages 3-4)

13. Prevention

Primary prevention of a de novo or inherited pathogenic allele is not possible through lifestyle change. Reproductive options after molecular diagnosis include genetic counseling, natural conception with or without prenatal diagnosis, donor gametes, adoption, and IVF with preimplantation genetic testing.

Secondary prevention comprises cascade testing and longitudinal audiology, particularly because phenotype-based screening may miss young, age-dependent carriers. Early amplification and educational intervention can reduce developmental and communication consequences.

Tertiary prevention includes hearing conservation, avoidance of unnecessary ototoxic exposure, optimized amplification, vaccination and infection prevention according to routine standards—especially before cochlear implantation—and maintenance of social/communication access. These measures prevent additive injury or complications; they do not correct SLC17A8.

14. Other species and natural disease

Orthologous Slc17a8 is conserved across vertebrates, and the p.A211 residue is conserved across species. Suggested taxa include Mus musculus (NCBI Taxonomy 10090), Rattus norvegicus (10116), Danio rerio (7955), and Homo sapiens (9606). (ruel2008impairmentofslc17a8 pages 1-2)

No well-validated, naturally occurring companion-animal or livestock counterpart attributable to an orthologous dominant SLC17A8 allele was identified; therefore no defensible VBO breed annotation or veterinary prevalence can be assigned. DFNA25 is noninfectious and has no zoonotic or cross-species transmission potential.

15. Model organisms

Slc17a8 knockout mouse

Targeted exon-2 deletion produces congenital profound deafness with absent acoustic auditory-nerve responses, preserved electrically evoked ABRs, and robust OAEs. Ca²⁺-triggered vesicle turnover remains intact at approximately two weeks, demonstrating that vesicle fusion can occur without glutamate loading. Afferent synapses, spiral-ganglion neurons, and lateral efferent terminals decline later. This model is excellent for transporter loss and gene-replacement studies but does not reproduce heterozygous, delayed-onset human p.A211V disease. (ruel2008impairmentofslc17a8 pages 12-13, ruel2008impairmentofslc17a8 pages 1-2)

p.A224V knock-in mouse

Mouse p.A224V models human p.A211V. Homozygous knock-in mice exhibit progressive ABR loss with preserved cochlear amplification, reduced summating potentials, IHC—but not OHC—stereociliary-bundle collapse, oversized ribbons, and increased sustained-pool exocytosis. The authors concluded that DFNA25 “stems from a failure in the mechano-transduction followed by a change in synaptic transfer.” Publication: December 2021; DOI 10.1113/JP282181. The homozygous design may exaggerate a heterozygous human phenotype. (joshi2021vglut3‐p.a211vvariantfuses pages 1-2)

Other model uses and limitations

VGLUT3-positive IHC organelle immunoisolation and cochlear explants support biochemical and cellular studies; zebrafish offer conserved hair-cell biology and regeneration but differ from mammalian cochlear frequency tuning and OHC specialization. No validated DFNA25 patient iPSC-derived IHC or cochlear-organoid model was identified.

Evidence appraisal and principal knowledge gaps

The causal gene–disease relationship is strong: linkage and segregation in human families align with highly specific knockout and knock-in physiology. Nevertheless, the clinical evidence base is small and family-biased. Major missing items are disease-specific prevalence, quantitative penetrance, variant-level natural history, prospective speech and quality-of-life outcomes, human cochlear-implant outcomes, validated environmental modifiers, patient-derived omics, and clinical therapeutic trials. The most important translational distinction is that successful replacement in a recessive/null mouse does not prove efficacy against a dominant human missense allele.

Key source list

  1. Ruel J, et al. Am J Hum Genet. Published 8 August 2008. DOI: 10.1016/j.ajhg.2008.07.008; PMID 18674745. (ruel2008impairmentofslc17a8 pages 1-2)
  2. Akil O, et al. Neuron. Published 26 July 2012. DOI: 10.1016/j.neuron.2012.05.019; PMID 22794260. (akil2012restorationofhearing pages 1-2)
  3. Ryu N, et al. BMC Medical Genetics. January 2016. DOI: 10.1186/s12881-016-0269-3. (ryu2016screeningofthe pages 1-2)
  4. Ryu N, et al. Gene. September 2017. DOI: 10.1016/j.gene.2017.06.040. (ryu2017identificationofa pages 1-6)
  5. Joshi Y, et al. Journal of Physiology. December 2021. DOI: 10.1113/JP282181. (joshi2021vglut3‐p.a211vvariantfuses pages 1-2)
  6. Cepeda AP, et al. Molecular & Cellular Proteomics. February 2024. DOI: 10.1016/j.mcpro.2023.100704. (cepeda2024proteomicanalysisreveals pages 1-3)
  7. Duhon BH, et al. Frontiers in Audiology and Otology. July 2024. DOI: 10.3389/fauot.2024.1423853. (duhon2024genetherapyadvancements pages 11-12, duhon2024genetherapyadvancements pages 4-5)
  8. Zhang L, et al. Advanced Science. November 2024. DOI: 10.1002/advs.202402166. (zhang2024aav‐mediatedgenetherapy pages 3-4)

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  12. (bottom2024defectsinhair pages 1-2): Riley T. Bottom, Yijun Xu, Caroline Siebald, Jinsei Jung, and Ulrich Müller. Defects in hair cells disrupt the development of auditory peripheral circuitry. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55275-x, doi:10.1038/s41467-024-55275-x. This article has 7 citations and is from a highest quality peer-reviewed journal.

  13. (ryu2017identificationofa pages 23-25): Nari Ryu, Seokwon Lee, Hong-Joon Park, Byeonghyeon Lee, Tae-Jun Kwon, Jinwoong Bok, Chan Ik Park, Kyu-Yup Lee, Jeong-In Baek, and Un-Kyung Kim. Identification of a novel splicing mutation within slc17a8 in a korean family with hearing loss by whole-exome sequencing. Gene, 627:233-238, Sep 2017. URL: https://doi.org/10.1016/j.gene.2017.06.040, doi:10.1016/j.gene.2017.06.040. This article has 16 citations and is from a peer-reviewed journal.

  14. (ruel2008impairmentofslc17a8 pages 12-13): Jérôme Ruel, Sarah Emery, Régis Nouvian, Tiphaine Bersot, Bénédicte Amilhon, Jana M. Van Rybroek, Guy Rebillard, Marc Lenoir, Michel Eybalin, Benjamin Delprat, Theru A. Sivakumaran, Bruno Giros, Salah El Mestikawy, Tobias Moser, Richard J.H. Smith, Marci M. Lesperance, and Jean-Luc Puel. Impairment of slc17a8 encoding vesicular glutamate transporter-3, vglut3, underlies nonsyndromic deafness dfna25 and inner hair cell dysfunction in null mice. American journal of human genetics, 83 2:278-92, Aug 2008. URL: https://doi.org/10.1016/j.ajhg.2008.07.008, doi:10.1016/j.ajhg.2008.07.008. This article has 345 citations and is from a highest quality peer-reviewed journal.

  15. (akil2012restorationofhearing pages 9-10): Omar Akil, Rebecca P. Seal, Kevin Burke, Chuansong Wang, Aurash Alemi, Matthew During, Robert H. Edwards, and Lawrence R. Lustig. Restoration of hearing in the vglut3 knockout mouse using virally mediated gene therapy. Neuron, 75:283-293, Jul 2012. URL: https://doi.org/10.1016/j.neuron.2012.05.019, doi:10.1016/j.neuron.2012.05.019. This article has 480 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 5
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:22794260 (1 mention) - Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons.
  • shared terms: none

Weighed against this report's own most characteristic terms: disease, human, dfna25, clinical, gene, loss, hearing, genetic, model, variant, slc17a8, dominant, cochlear, molecular, phenotype, allele, type, nonsyndromic, progressive, ihc.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 8
Resolved 8
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0011568 (3 mentions) - the report calls it "if available"; MONDO calls it autosomal dominant nonsyndromic hearing loss 25