Hearing Loss Autosomal Dominant 83

Mendelian MONDO:0030723 Pathograph 15 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA83 is progressive autosomal dominant nonsyndromic sensorineural hearing loss caused by heterozygous missense variants in MAP1B, which encodes a microtubule-associated phosphoprotein. It was defined in 2020 in three unrelated Chinese pedigrees found by whole exome sequencing of 863 genetically uncharacterised hearing-impaired probands. What makes this entry worth reading is not the gene but where the lesion sits. Almost every dominant deafness gene curated in this knowledge base acts on the hair cell. DFNA83 does not. Distortion product otoacoustic emissions, which report outer hair cell function, were indistinguishable between affected and hearing-normal individuals in the index family, and stayed normal in the mouse at every age tested out to 32 weeks while auditory brainstem response thresholds were already raised. Cochlear morphology in the mouse was likewise unremarkable, with no hair cell loss and no change in spiral ganglion neuron density. The deficit is functional and it is in the neuron: shorter neurites, hyperstabilised microtubules at the growth cone, reduced potassium currents and degraded action potentials. Allele class also carries unusual weight for this gene. MAP1B loss-of-function alleles cause a different disease, periventricular nodular heterotopia 9, a neuronal migration disorder; the deafness alleles are missense. That matters when reading the mouse work below, because the mouse is a null. That combination, raised ABR thresholds with preserved otoacoustic emissions, is the audiological signature of auditory neuropathy rather than of cochlear hearing loss, and it has a practical consequence: hearing aids that amplify sound into a cochlea whose hair cells work are addressing the wrong compartment. No management data exist for DFNA83, so this entry does not claim any. The evidence is unusually deep for a two-paper deafness locus, because the founding report carried its own isogenic rescue. Patient-derived induced pluripotent stem cells were differentiated into otic sensory neuron-like cells, the p.Ser1400Gly allele was corrected by CRISPR/Cas9 in a sister line, and every measured defect returned toward the control value. That is a within-experiment causality argument of a kind most entries here do not have. It is still one allele of the three, in one family, in one laboratory.

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1
Inheritance
6
Pathophys.
3
Phenotypes
3
Gaps
15
Pathograph
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Genes
3
Variants
2
Models
4
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Three heterozygous MAP1B missense alleles in three unrelated Chinese pedigrees. In the index family the variant was present in all seven affected members and absent from all thirteen unaffected members tested, and absent from 863 unrelated hearing-impaired probands and 206 hearing-normal controls. The other two alleles were absent from asymptomatic relatives and from the same 206 controls.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:33268592 SUPPORT Human Clinical
"Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families."
Co-segregation of three independent heterozygous alleles across three unrelated pedigrees, which is what establishes the dominant mode.
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Discussions and Knowledge Gaps

3
If DFNA83 is a spiral ganglion disorder with working outer hair cells, does hearing amplification help, and is a cochlear implant the better option? Nothing has been reported either way.
KNOWLEDGE GAP dfna83_auditory_neuropathy_management
Attached to
pathophysiology#Failure of Auditory Nerve Signal Transmission phenotypes#Abnormal auditory brainstem response with preserved otoacoustic emissions treatments#
This is the clinically consequential gap in the entry, and it follows directly from the mechanism rather than being a generic call for more research. A hearing aid amplifies sound so that a cochlea can transduce it. In DFNA83 the cochlea already transduces it, which is what the preserved otoacoustic emissions show; what fails is the neuron carrying the result to the brainstem. In other auditory neuropathies that configuration predicts poor benefit from amplification and better outcomes from cochlear implantation, which bypasses the hair cell and stimulates the ganglion directly. Whether that generalises to DFNA83 is unknown, and there is a specific reason to hesitate: implant performance depends on the health of the spiral ganglion neurons being stimulated, and those are precisely the cells this disease affects. The mouse offers a small piece of reassurance, since spiral ganglion neuron density was normal, so the target population may be present even if it fires poorly. The entry therefore carries no treatments section at all. That is a deliberate absence: the three published families were reported for gene discovery and no management outcome was recorded for any of them.
Show evidence (1 reference)
PMID:33268592 SUPPORT Human Clinical
"there were no significant difference of distortion product otoacoustic emissions (DPOAE) measurements between affected subjects and hearing-normal controls"
The audiological configuration that makes the management question a real one rather than a generic gap.
Two of the three reported DFNA83 alleles, p.Ile923Thr and p.Phe1838Leu, have never been tested in any experimental system. Do they act by the mechanism curated here?
KNOWLEDGE GAP dfna83_two_untested_alleles
Attached to
pathophysiology#Heterozygous MAP1B Missense Variants at Conserved Residues genetic#MAP1B
Everything in the pathophysiology section derives from p.Ser1400Gly, and there is a structural reason the other two might behave differently. Ser1400 was chosen for functional work precisely because it is a known phosphorylation site in the microtubule-assembly domain, so the phosphorylation deficit that drives the whole chain is a property of that residue's identity. Ile923 and Phe1838 are conserved but are not phosphosites, and a missense change at either could plausibly act through protein stability, microtubule binding affinity or something else entirely without ever reproducing the SMI-31 deficit. The reporting group said as much, classifying only p.Ser1400Gly as very likely deleterious and leaving the others as needing further exploration. Until somebody tests them, this entry describes the mechanism of one allele and asserts a shared gene for three.
Show evidence (1 reference)
PMID:33268592 SUPPORT Human Clinical
"Based on in silico predictions and the incidences of their variants in the general population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and p.1838F>L variants need to be further explored."
The authors' own differential assessment of the three alleles.
The mouse is a heterozygous null and the patients carry missense alleles. Is DFNA83 haploinsufficiency, or does the missense protein do something a null cannot?
HUMAN MODEL MISMATCH dfna83_null_mouse_versus_missense_human
Attached to
animal_models#Map1b heterozygous knockout mouse pathophysiology#Reduced MAP1B Level and Deficient Type I Phosphorylation
The mouse result is the strongest in vivo evidence in this entry, and its allele does not match the disease. The authors bridge that gap with biochemistry rather than genetics: heterozygous mouse brain has 69 percent of wild-type type I phosphorylation and patient-derived cells have 69 percent, so the two systems arrive at the same functional deficit by different routes. That is a reasonable argument and it is not the same as demonstrating that the human allele is a loss of function. Where it matters is the mutant protein itself. Patient cells retain 63 percent of normal MAP1B, so there is a substantial amount of Ser1400Gly protein present, binding microtubules while unable to be phosphorylated at that site. A null mouse has no such protein. If the human phenotype has any dominant negative component, from mutant MAP1B occupying microtubules it can no longer regulate, the mouse cannot show it and would understate the disease. The hyperstabilisation result is at least consistent with that reading, since removing a protein and jamming it in place are different ways to lose dynamism. There is now a much sharper reason to doubt the null mouse, and it postdates the founding paper. Human MAP1B loss-of-function alleles have their own phenotype, and it is not deafness: heterozygous truncating variants cause periventricular nodular heterotopia 9, a neuronal migration disorder. A 2025 review of the MAP1B genotype-phenotype literature concluded that loss-of-function variants mainly give PVNH-related neurological disease while missense variants may present with deafness alone. So the mouse used to prove DFNA83 in vivo carries the allele class that in humans causes a brain malformation instead. Either mouse and human differ in which tissue is dosage-limiting for MAP1B, or the human missense alleles are not acting by simple loss of function, and the two possibilities have opposite consequences for how much weight the mouse can bear. That does not make the mouse uninformative. Its dissociation of raised ABR thresholds from preserved otoacoustic emissions is a clean result and is the strongest evidence anywhere that the DFNA83 lesion is neural. But it means the mouse establishes what reduced MAP1B does to spiral ganglion neurons, not that the human alleles reduce MAP1B in the way the mouse does. A knock-in mouse carrying Ser1400Gly would settle it. None exists.
Show evidence (4 references)
PMID:33268592 SUPPORT Model Organism
"Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice."
States plainly that the in vivo confirmation came from a knockout rather than a knock-in, which is the mismatch.
PMID:33268592 SUPPORT In Vitro
"we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics"
The human allele's measured effect, which is partial protein reduction rather than absence, and therefore not equivalent to a null.
PMID:40802165 SUPPORT Human Clinical
"we found that loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
The allelic dichotomy in humans, which is what makes the null mouse a mismatched model rather than merely an imperfect one: human nulls give a brain malformation, not hearing loss.
+ 1 more reference
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Pathophysiology

6
Heterozygous MAP1B Missense Variants at Conserved Residues
Three alleles are reported: p.Ser1400Gly, p.Ile923Thr and p.Phe1838Leu, all at residues conserved across human, chimpanzee, macaque, dog, mouse and rat. Ser1400 sits in the microtubule-assembly domain at a phosphorylation site already known to be required for embryonic cortical neuron function, which is why it was the allele taken forward for functional work. The three alleles are not equally supported, and the entry does not pretend otherwise. The reporting group's own ACMG assessment called p.Ser1400Gly very likely deleterious and said the other two needed further exploration. Every functional result below is from p.Ser1400Gly. Allele class matters more here than it does for most deafness genes, because MAP1B has a second, non-auditory phenotype that separates by allele type rather than by position. Heterozygous loss-of-function alleles cause periventricular nodular heterotopia 9, a neuronal migration disorder, and a 2025 review of the MAP1B literature found that missense alleles are the ones that present with deafness alone. DFNA83 is therefore not simply the mild end of a MAP1B dosage spectrum, and treating it as haploinsufficiency would predict the wrong disease.
MAP1B hgnc:6836 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAP1B (hgnc:6836). hgnc:6836 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced MAP1B Level and Deficient Type I Phosphorylation
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Based on in silico predictions and the incidences of their variants in the general population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and p.1838F>L variants need to be further explored."
The authors' own differential confidence across the three alleles, which is why this entry attributes all downstream mechanism to p.Ser1400Gly alone.
PMID:40802165 SUPPORT Human Clinical
"PVNH9 is caused by a heterozygous mutation in the microtubule-associated protein 1B (MAP1B) gene."
Establishes that MAP1B has a second heterozygous phenotype, which is what makes the allele class of a DFNA83 variant a substantive rather than a descriptive fact.
Reduced MAP1B Level and Deficient Type I Phosphorylation
In patient-derived otic sensory neuron-like cells the mutant allele reduced total MAP1B protein to 63 percent of control and type I phosphorylation, detected with SMI-31, to 69 percent. Both were restored in the CRISPR-corrected isogenic line, to 90 and 96 percent. The same phosphorylation deficit was reproduced in the brain of heterozygous Map1b knockout mice, at 69 percent of wild-type littermates, which is the observation the authors use to argue the mouse recapitulates the patient biochemistry rather than merely sharing a gene.
protein phosphorylation GO:0006468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein phosphorylation (GO:0006468). GO:0006468 is a biological process from the Gene Ontology. ↓ DECREASED
microtubule binding GO:0008017 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased microtubule binding (GO:0008017). GO:0008017 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Microtubule Hyperstabilisation in the Growth Cone
Show evidence (1 reference)
PMID:33268592 SUPPORT In Vitro
"we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics"
The primary biochemical consequence of the allele, measured in patient-derived cells.
Microtubule Hyperstabilisation in the Growth Cone
The counterintuitive step. Losing a microtubule-associated protein makes the cytoskeleton more stable, not less: acetylated alpha-tubulin, a marker of stabilised microtubules, rose to 168 percent of control in mutant cells and was elevated specifically in the growth cones of developing axons, and mutant cells resisted depolymerisation by vinblastine. Phosphorylated MAP1B maintains the pool of dynamic microtubules, so losing that phosphorylation removes dynamism rather than structure. The corrected line returned to 75 percent of control. Growth cone steering and axon extension require microtubules that can depolymerise as well as polymerise, which is the mechanistic reason a stabilised cytoskeleton is a defect here.
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.
microtubule cytoskeleton organization GO:0000226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal microtubule cytoskeleton organization (GO:0000226). GO:0000226 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Neurite Extension in Spiral Ganglion Neurons
Altered Spiral Ganglion Neuron Excitability The link from cytoskeletal state to membrane excitability is asserted by co-occurrence in the same cells rather than by a demonstrated route. Both are corrected together by the isogenic rescue, which constrains but does not identify the intermediates.
Show evidence (2 references)
PMID:33268592 SUPPORT In Vitro
"The increased levels of acetylated-tubulin implied that the p.1400S>G mutation caused the disturbing dynamics of microtubules."
The acetylation measurement and the authors' reading of its direction.
PMID:33268592 SUPPORT In Vitro
"marked increases in acetylation of α-tubulin were observed in the growth cones of developing axons carrying the p.1400S>G mutation"
Localises the cytoskeletal change to the growth cone, which is what connects it to the neurite extension defect below.
Impaired Neurite Extension in Spiral Ganglion Neurons
Neurites were 30 percent shorter in mutant patient-derived otic neurons than in control ones, and the corrected line was indistinguishable from control. Primary spiral ganglion neurons isolated from heterozygous Map1b mice showed the same thing, at roughly half the wild-type neurite length. Fewer mutant cells extended any neurite at all.
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.
axon extension GO:0048675 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axon extension (GO:0048675). GO:0048675 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived iPSC otic sensory neuron-like cells with isogenic CRISPR correction IPSC DERIVED MODEL Mutant neurites averaged 140 micrometres against 198 in control, a 30 percent reduction, with the corrected line at 187.
Downstream
Failure of Auditory Nerve Signal Transmission
Show evidence (2 references)
PMID:33268592 SUPPORT In Vitro
"The loss of MAP1B shortened the neurite lengths in SGNs; the average lengths of neurites in neonatal Map1b+/– mice were 126.9 ± 8.1 μm (n = 58), while those of Map1b+/+ mice were 228.3 ± 10.7 μm (n = 57)"
The neurite length measurement in primary mouse spiral ganglion neurons, with the control value and sample sizes.
PMID:33268592 SUPPORT In Vitro
"Elevated levels of acetylated α-tubulin in these highly dynamic and motile structures at the leading edge of developing axons indicated a potential restriction of axon elongation."
The authors' link from the cytoskeletal state to the elongation defect. Note the hedge in their own wording.
Altered Spiral Ganglion Neuron Excitability
Whole-cell patch clamp in both systems found the same pattern: reduced spike amplitude, prolonged spike width, longer latency, a raised action potential threshold, and reduced outward potassium current. In mouse spiral ganglion neurons the peak potassium current density at 60 millivolts was 48 percent of wild type. In patient-derived neurons every one of these parameters was restored by CRISPR correction of the allele. This is the node that most directly explains the audiogram, because a spiral ganglion neuron that fires late, small and blunt will degrade the auditory brainstem response while leaving cochlear amplification untouched.
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.
action potential GO:0001508 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal action potential (GO:0001508). GO:0001508 is a biological process from the Gene Ontology. ⚠ ABNORMAL potassium ion transmembrane transport GO:0071805 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased potassium ion transmembrane transport (GO:0071805). GO:0071805 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived iPSC otic sensory neuron-like cells with isogenic CRISPR correction IPSC DERIVED MODEL Correcting the allele restored spike amplitude, width, latency, threshold and potassium current to values comparable with the unrelated control line. Because the corrected line is isogenic, this is a causality argument about the variant rather than an association between genotype and phenotype across lines.
Animal models
Map1b heterozygous knockout mouse Mouse recapitulates Primary spiral ganglion neurons isolated from heterozygous mice reproduce the human cell phenotype directly: shortened neurites, elevated growth cone alpha-tubulin acetylation, reduced outward potassium current and degraded action potentials.
Downstream
Failure of Auditory Nerve Signal Transmission
Show evidence (2 references)
PMID:33268592 SUPPORT In Vitro
"Peak outward K+ current densities at all test potentials are significantly (P < 0.001) lower in Map1b+/– SGNs than those in WT SGNs"
The potassium current deficit in primary mouse spiral ganglion neurons.
PMID:33268592 SUPPORT In Vitro
"otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties"
The same electrophysiological phenotype in patient-derived human cells, which is what makes the mouse finding more than a species observation.
Failure of Auditory Nerve Signal Transmission
The organ-level consequence: sound is transduced normally by the cochlea but the representation that reaches the brainstem is degraded. In the mouse this appears as raised auditory brainstem response thresholds at every frequency and age tested, with distortion product otoacoustic emissions unaffected throughout and no hair cell loss on cochlear histology. In patients it appears as sensorineural hearing loss with normal otoacoustic emissions.
cochlear nerve UBERON:0004727 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlear nerve (UBERON:0004727). UBERON:0004727 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Map1b heterozygous knockout mouse Mouse recapitulates The mouse is where the dissociation between neural and cochlear function is established. ABR thresholds are raised at every frequency and age tested from 4 to 32 weeks, DPOAEs are unimpaired throughout, and cochlear histology shows neither hair cell loss nor reduced spiral ganglion neuron density. That is not merely consistent with a neuronal lesion, it excludes the cochlear alternative in this species.
Downstream
Progressive sensorineural hearing impairment
High-frequency predominant hearing loss
Abnormal auditory brainstem response with preserved otoacoustic emissions
Show evidence (2 references)
PMID:33268592 SUPPORT Model Organism
"Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by MAP1B deficiency caused hearing loss."
The paper's central conclusion, which is the claim this node states.
PMID:33268592 SUPPORT Model Organism
"Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice."
The negative half of the claim, which is what places the lesion in the neuron rather than the cochlear sensory epithelium.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hearing Loss Autosomal Dominant 83 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Ear 2
Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408), qualified as course progressive. HP:0000408 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Seven of 21 members in this family exhibited bilateral sensorineural hearing impairment as a sole clinical phenotype."
The human phenotype and its restriction to hearing, which is what makes DFNA83 nonsyndromic.
PMID:33268592 SUPPORT Human Clinical
"Members of this family displayed the late-onset/progressive hearing impairment with variable severity and age at onset"
Onset and course, including the intrafamilial variability that no genotype currently explains.
High-frequency predominant hearing loss High-frequency hearing impairment HP:0005101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency hearing impairment (HP:0005101). HP:0005101 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33268592 SUPPORT Model Organism
"These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies."
The frequency profile in the mouse. Graded MODEL_ORGANISM and kept separate from the human phenotype above because the tonotopic detail comes from the animal.
Nervous System 1
Abnormal auditory brainstem response with preserved otoacoustic emissions Abnormal auditory evoked potentials HP:0006958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal auditory evoked potentials (HP:0006958). HP:0006958 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"there were no significant difference of distortion product otoacoustic emissions (DPOAE) measurements between affected subjects and hearing-normal controls"
The human otoacoustic emission result, which is one half of the dissociation this phenotype names. HPO has no auditory-neuropathy term and no term for preserved emissions, so the binding is to the abnormal auditory evoked potential term, which is accurate for the raised brainstem thresholds that make up the other half.
PMID:33268592 SUPPORT Model Organism
"DPOAE (8, 12, 24, and 32 kHz) was not impaired in the 4-, 8-, 16-, or 32-week-old Map1b+/– mice (5 males, 5 females), as compared with WT mice (5 males, 5 females)."
The same negative result in the mouse across the full age range, with the sample sizes.
🧬

Genetic Associations

1
MAP1B
Gene: MAP1B hgnc:6836 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAP1B (hgnc:6836). hgnc:6836 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Based on in silico predictions and the incidences of their variants in the general population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and p.1838F>L variants need to be further explored."
The reporting group's differential assessment, which is the basis for the three clinical_significance values recorded above.
PMID:33268592 SUPPORT Model Organism
"Strikingly, Map1b is abundantly expressed in the spiral ganglions but is weak in hair cells."
The expression asymmetry that predicts the cell type in which the lesion acts. Measured in mouse cochlea by immunofluorescence.
Variants (3)
NM_005909.4:c.4198A>G (p.Ser1400Gly) Likely Pathogenic
missense
The founding allele, in the microtubule-assembly domain at a conserved phosphorylation site required for embryonic cortical neuron function. Present in all seven affected and none of thirteen unaffected members of the index pedigree, and absent from 863 unrelated hearing-impaired probands and 206 hearing-normal controls. This is the only DFNA83 allele with functional data: it reduces MAP1B protein to 63 percent of control and type I phosphorylation to 69 percent, and correcting it by CRISPR restores both. Recorded as LIKELY_PATHOGENIC because that is the reporting group's own assessment, which called it very likely deleterious rather than definitively so.
NM_005909.4:c.2768T>C (p.Ile923Thr) Uncertain Significance
missense
Found in the SD061 pedigree, present in affected and absent from asymptomatic members and from 206 hearing-normal controls. At a conserved residue but not a phosphosite, and untested in any experimental system. The reporting group said it needed further exploration, which is why it is recorded as uncertain here rather than inheriting the founding allele's classification.
NM_005909.4:c.5512T>C (p.Phe1838Leu) Uncertain Significance
missense
Found in the SD234 pedigree, with the same segregation and control data and the same absence of functional testing as p.Ile923Thr.
🗃️

External Assertions

1
OMIM deafness, autosomal dominant 83 record
OMIM disease record OMIM:619808
OMIM entry for DFNA83, the MAP1B-related autosomal dominant nonsyndromic hearing loss phenotype curated here.
🔬

Diagnosis

1
Gene panel or exome sequencing, prompted by a neural audioprofile
DFNA83 has no distinguishing clinical feature outside the ear and cannot be diagnosed without sequencing. In the founding families a targeted panel of 89 known deafness-associated genes returned nothing, and the gene was found only on whole exome sequencing, so an older or narrower panel will not contain MAP1B. What can be done before sequencing is to narrow the differential. The audiological signature of DFNA83 is a dissociation: raised auditory brainstem response thresholds with distortion product otoacoustic emissions indistinguishable from hearing-normal controls. That pattern is the pattern of auditory neuropathy rather than of the hair cell disorders that account for most dominant deafness, and it is what led the founding group to look at spiral ganglion biology in the first place. A patient with dominant progressive sensorineural loss and preserved emissions is a reason to sequence broadly rather than to re-run a hair cell panel.
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Initial targeting exome sequencing analyses of 89 reported deafness-associated genes failed to identify any mutations"
Why a targeted panel is not sufficient: the established deafness gene set did not contain the answer in the founding family.
PMID:33268592 SUPPORT Human Clinical
"These suggested that the hearing impairment of these affected members may result from the dysfunctions in the spiral ganglia neurons."
The inference the audiological pattern licenses, drawn by the reporting group from their own DPOAE result. It is what makes the audioprofile diagnostically useful rather than merely descriptive.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Three unrelated Chinese pedigrees in the founding 2020 report, found by whole exome sequencing of 863 genetically uncharacterised hearing-impaired probands. No further family has been reported and no population estimate exists. The founding allele was absent from the remaining 863 probands and from 206 hearing-normal controls on Sanger sequencing, so it is not a common variant in the population it was found in; the other two alleles were likewise absent from those 206 controls.
Show evidence (2 references)
PMID:33268592 SUPPORT Human Clinical
"Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families."
The size of the reported literature, which is the whole of it.
PMID:33268592 SUPPORT Human Clinical
"We further analyzed the presence of the MAP1B c.4198A>G mutation in a cohort of 863 genetically unrelated hearing-impaired probands and 206 unrelated hearing-normal individuals by Sanger sequencing. We failed to detect the c.4198A>G mutation in all these hearing-normal and hearing-impaired individuals."
The rarity of the founding allele within the cohort it was discovered in, which is the only quantitative rarity statement available for this disorder.
🧫

Experimental Models

1
Patient-derived iPSC otic sensory neuron-like cells with isogenic CRISPR correction IPSC_DERIVED_MODEL
Induced pluripotent stem cells were reprogrammed from peripheral blood mononuclear cells of the affected proband and of a married-in hearing-normal family member, then differentiated stepwise into otic sensory neuron-like cells. A third line was made by correcting the p.Ser1400Gly allele in the patient line with CRISPR/Cas9, giving an isogenic control that differs from the mutant line at one base. The three-line design is what raises this above a patient-cell description: mutant, unrelated control, and corrected isogenic sibling. Every defect measured moved back toward control in the corrected line.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Pathograph links
Altered Spiral Ganglion Neuron Excitability rescues fidelity: moderate observes: cellular Correcting the allele restored spike amplitude, width, latency, threshold and potassium current to values comparable with the unrelated control line. Because the corrected line is isogenic, this is a causality argument about the variant rather than an association between genotype and phenotype across lines.
Limitations: Otic sensory neuron-like cells are a directed differentiation product, not spiral ganglion neurons; the paper is careful to call them neuron-like. They are also immature, dissociated and outside a cochlea, so the tonotopy and the progressive adult-onset course that define the human disease cannot be modelled here at all. Only one of the three DFNA83 alleles was tested.
Divergences from the human mechanism
boundary omission qualifying
The cochlear environment is outside the model. Hair cell input, ribbon synapses, the tonotopic gradient and the endocochlear potential are all absent, so the model cannot report on how a neuronal excitability deficit becomes a frequency-specific threshold shift.
population mismatch qualifying
Every line derives from one family and one allele, p.Ser1400Gly. The two other reported DFNA83 alleles, p.Ile923Thr and p.Phe1838Leu, are untested in any system.
Readouts
Action potential amplitude, width, latency and activation threshold
Direction: RESTORED
Interpretation: In the mutant line spike amplitude fell to 42 percent of control, width rose to 196 percent, latency to 145 percent and threshold to 139 percent; the corrected line was comparable with control on all four.
Show evidence (1 reference)
PMID:33268592 SUPPORT In Vitro
"Dysfunctions of these derived otic sensory neuron-like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology."
The rescue result that this readout records.
Impaired Neurite Extension in Spiral Ganglion Neurons recapitulates fidelity: moderate observes: cellular Mutant neurites averaged 140 micrometres against 198 in control, a 30 percent reduction, with the corrected line at 187.
Limitations: Neurite length in a dish is a proxy for peripheral process integrity in the cochlea, which was not measured in humans and cannot be.
Readouts
Neurite length in differentiated otic sensory neuron-like cells
Direction: DECREASED
Interpretation: A 30 percent shortening, reversed by correction of the allele.
Show evidence (1 reference)
PMID:33268592 SUPPORT In Vitro
"otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties"
The elongation defect stated in the abstract alongside the cytoskeletal and electrophysiological ones.
Show evidence (1 reference)
PMID:33268592 SUPPORT In Vitro
"Using otic sensory neuron-like cells, generated by pluripotent stem cells from patients carrying the MAP1B mutation and control subject, we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B"
Attests that this model system was informative for the mechanism, which is the claim a link-level evidence item has to make. It names the model, its provenance from patient and control subjects, and the result it produced.
🐁

Animal Models

1
Map1b heterozygous knockout mouse
A CRISPR-generated frameshift null. Heterozygotes are viable; homozygotes survive only about ten days after birth, so all auditory work is in the heterozygote. Heterozygous brain has 40 percent less MAP1B protein and 69 percent of wild-type type I phosphorylation, matching the biochemical deficit measured in patient-derived cells.
Species
Mouse
Genotype
Map1b+/-, CRISPR/Cas9 frameshift producing p.Leu139*
Genes
MAP1B hgnc:6836 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MAP1B (hgnc:6836). hgnc:6836 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33268592
Pathograph links
Failure of Auditory Nerve Signal Transmission recapitulates fidelity: moderate observes: organism The mouse is where the dissociation between neural and cochlear function is established. ABR thresholds are raised at every frequency and age tested from 4 to 32 weeks, DPOAEs are unimpaired throughout, and cochlear histology shows neither hair cell loss nor reduced spiral ganglion neuron density. That is not merely consistent with a neuronal lesion, it excludes the cochlear alternative in this species.
Limitations: Allele mismatch is the main gap: the mouse is a heterozygous null, whereas the human alleles are missense changes at conserved residues whose mode of action, whether haploinsufficiency or something else, has not been established. The paper's own argument for equivalence is the shared phosphorylation deficit rather than a matched allele. Mouse onset is also earlier relative to lifespan, with thresholds already raised at 4 weeks, against late onset in the human families.
Divergences from the human mechanism
proxy quantity qualifying
The manipulated quantity is Map1b gene dosage, halved by a null allele. The human quantity is the activity of a missense MAP1B protein present at 63 percent of normal with disproportionately reduced phosphorylation. These are similar in direction but not the same lesion, and a missense protein can retain or distort functions a null cannot.
Readouts
Auditory brainstem response threshold
Direction: INCREASED
Interpretation: Raised at click and at 8, 12, 24 and 32 kHz in heterozygotes at every age tested, with slow progression from 4 to 32 weeks.
Show evidence (1 reference)
PMID:33268592 SUPPORT Model Organism
"These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies."
The auditory phenotype this readout measures.
Distortion product otoacoustic emission threshold
Direction: UNCHANGED
Interpretation: A real negative result, and the one that makes the lesion neural. Outer hair cell function is preserved at every age at which ABR thresholds are already raised.
Show evidence (1 reference)
PMID:33268592 SUPPORT Model Organism
"DPOAE (8, 12, 24, and 32 kHz) was not impaired in the 4-, 8-, 16-, or 32-week-old Map1b+/– mice (5 males, 5 females), as compared with WT mice (5 males, 5 females)."
The preserved cochlear amplification, with ages and sample sizes.
Cochlear hair cell morphology and spiral ganglion neuron density
Direction: UNCHANGED
Interpretation: Phalloidin staining of the organ of Corti showed no hair cell loss or bundle abnormality, and spiral ganglion neuron density was unchanged. The deficit is functional, not degenerative, at least at the ages examined.
Show evidence (1 reference)
PMID:33268592 SUPPORT Model Organism
"the phalloidin staining revealed no apparent morphological abnormality or hair cell loss in middle turn, apex, and basal turns of cochlea in Map1b+/– mice at the age of P30"
The cochlear histology that excludes a structural sensory lesion.
Show evidence (1 reference)
PMID:33268592 SUPPORT Model Organism
"Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice."
The model's central conclusion, positive and negative halves together, which is what licenses linking it to this node.
Altered Spiral Ganglion Neuron Excitability recapitulates fidelity: moderate observes: cellular Primary spiral ganglion neurons isolated from heterozygous mice reproduce the human cell phenotype directly: shortened neurites, elevated growth cone alpha-tubulin acetylation, reduced outward potassium current and degraded action potentials.
Limitations: Neurons were isolated at postnatal day 5, before the mouse hearing onset and decades earlier in developmental terms than the human disease presents, so the recording is of a developing neuron rather than of the mature neuron that fails in patients.
Readouts
Peak outward potassium current density in isolated spiral ganglion neurons
Direction: DECREASED
Interpretation: 48 percent of wild-type at a 60 millivolt test potential.
Show evidence (1 reference)
PMID:33268592 SUPPORT In Vitro
"Peak outward K+ current densities at all test potentials are significantly (P < 0.001) lower in Map1b+/– SGNs than those in WT SGNs"
The current measurement behind this readout.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Dominant 83
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- DFNA83
- deafness, autosomal dominant 83
- MAP1B-related autosomal dominant nonsyndromic hearing loss
description: >-
  DFNA83 is progressive autosomal dominant nonsyndromic sensorineural hearing loss caused
  by heterozygous missense variants in MAP1B, which encodes a microtubule-associated
  phosphoprotein. It was defined in 2020 in three unrelated Chinese pedigrees found by
  whole exome sequencing of 863 genetically uncharacterised hearing-impaired probands.

  What makes this entry worth reading is not the gene but where the lesion sits. Almost
  every dominant deafness gene curated in this knowledge base acts on the hair cell.
  DFNA83 does not. Distortion product otoacoustic emissions, which report outer hair cell
  function, were indistinguishable between affected and hearing-normal individuals in the
  index family, and stayed normal in the mouse at every age tested out to 32 weeks while
  auditory brainstem response thresholds were already raised. Cochlear morphology in the
  mouse was likewise unremarkable, with no hair cell loss and no change in spiral ganglion
  neuron density. The deficit is functional and it is in the neuron: shorter neurites,
  hyperstabilised microtubules at the growth cone, reduced potassium currents and degraded
  action potentials.

  Allele class also carries unusual weight for this gene. MAP1B loss-of-function alleles
  cause a different disease, periventricular nodular heterotopia 9, a neuronal migration
  disorder; the deafness alleles are missense. That matters when reading the mouse work
  below, because the mouse is a null.

  That combination, raised ABR thresholds with preserved otoacoustic emissions, is the
  audiological signature of auditory neuropathy rather than of cochlear hearing loss, and
  it has a practical consequence: hearing aids that amplify sound into a cochlea whose
  hair cells work are addressing the wrong compartment. No management data exist for
  DFNA83, so this entry does not claim any.

  The evidence is unusually deep for a two-paper deafness locus, because the founding
  report carried its own isogenic rescue. Patient-derived induced pluripotent stem cells
  were differentiated into otic sensory neuron-like cells, the p.Ser1400Gly allele was
  corrected by CRISPR/Cas9 in a sister line, and every measured defect returned toward the
  control value. That is a within-experiment causality argument of a kind most entries
  here do not have. It is still one allele of the three, in one family, in one laboratory.
disease_term:
  preferred_term: hearing loss, autosomal dominant 83
  term:
    id: MONDO:0030723
    label: hearing loss, autosomal dominant 83
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
external_assertions:
- name: OMIM deafness, autosomal dominant 83 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:619808
  description: >-
    OMIM entry for DFNA83, the MAP1B-related autosomal dominant nonsyndromic hearing loss
    phenotype curated here.
inheritance:
- name: Autosomal dominant
  description: >-
    Three heterozygous MAP1B missense alleles in three unrelated Chinese pedigrees. In the
    index family the variant was present in all seven affected members and absent from all
    thirteen unaffected members tested, and absent from 863 unrelated hearing-impaired
    probands and 206 hearing-normal controls. The other two alleles were absent from
    asymptomatic relatives and from the same 206 controls.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families."
    explanation: >-
      Co-segregation of three independent heterozygous alleles across three unrelated
      pedigrees, which is what establishes the dominant mode.
pathophysiology:
- name: Heterozygous MAP1B Missense Variants at Conserved Residues
  description: >-
    Three alleles are reported: p.Ser1400Gly, p.Ile923Thr and p.Phe1838Leu, all at residues
    conserved across human, chimpanzee, macaque, dog, mouse and rat. Ser1400 sits in the
    microtubule-assembly domain at a phosphorylation site already known to be required for
    embryonic cortical neuron function, which is why it was the allele taken forward for
    functional work.

    The three alleles are not equally supported, and the entry does not pretend otherwise.
    The reporting group's own ACMG assessment called p.Ser1400Gly very likely deleterious
    and said the other two needed further exploration. Every functional result below is
    from p.Ser1400Gly.

    Allele class matters more here than it does for most deafness genes, because MAP1B has
    a second, non-auditory phenotype that separates by allele type rather than by position.
    Heterozygous loss-of-function alleles cause periventricular nodular heterotopia 9, a
    neuronal migration disorder, and a 2025 review of the MAP1B literature found that
    missense alleles are the ones that present with deafness alone. DFNA83 is therefore not
    simply the mild end of a MAP1B dosage spectrum, and treating it as haploinsufficiency
    would predict the wrong disease.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MAP1B
    term:
      id: hgnc:6836
      label: MAP1B
  downstream:
  - target: Reduced MAP1B Level and Deficient Type I Phosphorylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on in silico predictions and the incidences of their variants in the general population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and p.1838F>L variants need to be further explored."
    explanation: >-
      The authors' own differential confidence across the three alleles, which is why this
      entry attributes all downstream mechanism to p.Ser1400Gly alone.
  - reference: PMID:40802165
    reference_title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PVNH9 is caused by a heterozygous mutation in the microtubule-associated protein 1B (MAP1B) gene."
    explanation: >-
      Establishes that MAP1B has a second heterozygous phenotype, which is what makes the
      allele class of a DFNA83 variant a substantive rather than a descriptive fact.
- name: Reduced MAP1B Level and Deficient Type I Phosphorylation
  description: >-
    In patient-derived otic sensory neuron-like cells the mutant allele reduced total MAP1B
    protein to 63 percent of control and type I phosphorylation, detected with SMI-31, to
    69 percent. Both were restored in the CRISPR-corrected isogenic line, to 90 and 96
    percent. The same phosphorylation deficit was reproduced in the brain of heterozygous
    Map1b knockout mice, at 69 percent of wild-type littermates, which is the observation
    the authors use to argue the mouse recapitulates the patient biochemistry rather than
    merely sharing a gene.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: microtubule binding
    term:
      id: GO:0008017
      label: microtubule binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  downstream:
  - target: Microtubule Hyperstabilisation in the Growth Cone
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics"
    explanation: >-
      The primary biochemical consequence of the allele, measured in patient-derived cells.
- name: Microtubule Hyperstabilisation in the Growth Cone
  description: >-
    The counterintuitive step. Losing a microtubule-associated protein makes the
    cytoskeleton more stable, not less: acetylated alpha-tubulin, a marker of stabilised
    microtubules, rose to 168 percent of control in mutant cells and was elevated
    specifically in the growth cones of developing axons, and mutant cells resisted
    depolymerisation by vinblastine. Phosphorylated MAP1B maintains the pool of dynamic
    microtubules, so losing that phosphorylation removes dynamism rather than structure.
    The corrected line returned to 75 percent of control.

    Growth cone steering and axon extension require microtubules that can depolymerise as
    well as polymerise, which is the mechanistic reason a stabilised cytoskeleton is a
    defect here.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: ABNORMAL
  downstream:
  - target: Impaired Neurite Extension in Spiral Ganglion Neurons
    causal_link_type: DIRECT
  - target: Altered Spiral Ganglion Neuron Excitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The link from cytoskeletal state to membrane excitability is asserted by
      co-occurrence in the same cells rather than by a demonstrated route. Both are
      corrected together by the isogenic rescue, which constrains but does not identify
      the intermediates.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The increased levels of acetylated-tubulin implied that the p.1400S>G mutation caused the disturbing dynamics of microtubules."
    explanation: The acetylation measurement and the authors' reading of its direction.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "marked increases in acetylation of α-tubulin were observed in the growth cones of developing axons carrying the p.1400S>G mutation"
    explanation: >-
      Localises the cytoskeletal change to the growth cone, which is what connects it to
      the neurite extension defect below.
- name: Impaired Neurite Extension in Spiral Ganglion Neurons
  description: >-
    Neurites were 30 percent shorter in mutant patient-derived otic neurons than in control
    ones, and the corrected line was indistinguishable from control. Primary spiral ganglion
    neurons isolated from heterozygous Map1b mice showed the same thing, at roughly half the
    wild-type neurite length. Fewer mutant cells extended any neurite at all.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  biological_processes:
  - preferred_term: axon extension
    term:
      id: GO:0048675
      label: axon extension
    modifier: DECREASED
  downstream:
  - target: Failure of Auditory Nerve Signal Transmission
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The loss of MAP1B shortened the neurite lengths in SGNs; the average lengths of neurites in neonatal Map1b+/– mice were 126.9 ± 8.1 μm (n = 58), while those of Map1b+/+ mice were 228.3 ± 10.7 μm (n = 57)"
    explanation: >-
      The neurite length measurement in primary mouse spiral ganglion neurons, with the
      control value and sample sizes.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Elevated levels of acetylated α-tubulin in these highly dynamic and motile structures at the leading edge of developing axons indicated a potential restriction of axon elongation."
    explanation: >-
      The authors' link from the cytoskeletal state to the elongation defect. Note the
      hedge in their own wording.
- name: Altered Spiral Ganglion Neuron Excitability
  description: >-
    Whole-cell patch clamp in both systems found the same pattern: reduced spike amplitude,
    prolonged spike width, longer latency, a raised action potential threshold, and reduced
    outward potassium current. In mouse spiral ganglion neurons the peak potassium current
    density at 60 millivolts was 48 percent of wild type. In patient-derived neurons every
    one of these parameters was restored by CRISPR correction of the allele.

    This is the node that most directly explains the audiogram, because a spiral ganglion
    neuron that fires late, small and blunt will degrade the auditory brainstem response
    while leaving cochlear amplification untouched.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: ABNORMAL
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  downstream:
  - target: Failure of Auditory Nerve Signal Transmission
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Peak outward K+ current densities at all test potentials are significantly (P < 0.001) lower in Map1b+/– SGNs than those in WT SGNs"
    explanation: The potassium current deficit in primary mouse spiral ganglion neurons.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties"
    explanation: >-
      The same electrophysiological phenotype in patient-derived human cells, which is what
      makes the mouse finding more than a species observation.
- name: Failure of Auditory Nerve Signal Transmission
  description: >-
    The organ-level consequence: sound is transduced normally by the cochlea but the
    representation that reaches the brainstem is degraded. In the mouse this appears as
    raised auditory brainstem response thresholds at every frequency and age tested, with
    distortion product otoacoustic emissions unaffected throughout and no hair cell loss on
    cochlear histology. In patients it appears as sensorineural hearing loss with normal
    otoacoustic emissions.
  biological_scale: ORGANISM
  locations:
  - preferred_term: cochlear nerve
    term:
      id: UBERON:0004727
      label: cochlear nerve
  downstream:
  - target: Progressive sensorineural hearing impairment
    causal_link_type: DIRECT
  - target: High-frequency predominant hearing loss
    causal_link_type: DIRECT
  - target: Abnormal auditory brainstem response with preserved otoacoustic emissions
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by MAP1B deficiency caused hearing loss."
    explanation: The paper's central conclusion, which is the claim this node states.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice."
    explanation: >-
      The negative half of the claim, which is what places the lesion in the neuron rather
      than the cochlear sensory epithelium.
phenotypes:
- name: Progressive sensorineural hearing impairment
  category: Auditory
  description: >-
    Bilateral sensorineural hearing loss as the sole clinical phenotype, affecting seven of
    twenty-one members of the index pedigree. Onset is late and severity varies within the
    family. The mouse counterpart is more pronounced at high frequencies.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of 21 members in this family exhibited bilateral sensorineural hearing impairment as a sole clinical phenotype."
    explanation: >-
      The human phenotype and its restriction to hearing, which is what makes DFNA83
      nonsyndromic.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Members of this family displayed the late-onset/progressive hearing impairment with variable severity and age at onset"
    explanation: >-
      Onset and course, including the intrafamilial variability that no genotype currently
      explains.
- name: High-frequency predominant hearing loss
  category: Auditory
  description: >-
    Recorded from the mouse rather than from patient audiograms, where the published data
    are in supplementary material rather than the main text. Heterozygous Map1b mice have
    late-onset progressive loss that is worse in the high frequencies.
  phenotype_term:
    preferred_term: High-frequency hearing impairment
    term:
      id: HP:0005101
      label: High-frequency hearing impairment
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies."
    explanation: >-
      The frequency profile in the mouse. Graded MODEL_ORGANISM and kept separate from the
      human phenotype above because the tonotopic detail comes from the animal.
- name: Abnormal auditory brainstem response with preserved otoacoustic emissions
  category: Auditory
  description: >-
    The discriminating finding, and the node is named for the dissociation rather than for
    the emissions alone, because that is what the HPO binding can carry. DPOAEs report outer
    hair cell function, and they were not
    significantly different between affected and hearing-normal individuals in the index
    family, and were unimpaired in heterozygous Map1b mice at 4, 8, 16 and 32 weeks while
    their ABR thresholds were already raised. Raised ABR thresholds with preserved
    emissions is the pattern of auditory neuropathy, and it is the opposite of what most
    dominant deafness genes produce.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there were no significant difference of distortion product otoacoustic emissions (DPOAE) measurements between affected subjects and hearing-normal controls"
    explanation: >-
      The human otoacoustic emission result, which is one half of the dissociation this
      phenotype names. HPO has no auditory-neuropathy term and no term for preserved
      emissions, so the binding is to the abnormal auditory evoked potential term, which
      is accurate for the raised brainstem thresholds that make up the other half.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DPOAE (8, 12, 24, and 32 kHz) was not impaired in the 4-, 8-, 16-, or 32-week-old Map1b+/– mice (5 males, 5 females), as compared with WT mice (5 males, 5 females)."
    explanation: >-
      The same negative result in the mouse across the full age range, with the sample
      sizes.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three unrelated Chinese pedigrees in the founding 2020 report, found by whole exome
    sequencing of 863 genetically uncharacterised hearing-impaired probands. No further
    family has been reported and no population estimate exists. The founding allele was
    absent from the remaining 863 probands and from 206 hearing-normal controls on Sanger
    sequencing, so it is not a common variant in the population it was found in; the other
    two alleles were likewise absent from those 206 controls.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families."
    explanation: The size of the reported literature, which is the whole of it.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We further analyzed the presence of the MAP1B c.4198A>G mutation in a cohort of 863
      genetically unrelated hearing-impaired probands and 206 unrelated hearing-normal
      individuals by Sanger sequencing. We failed to detect the c.4198A>G mutation in all
      these hearing-normal and hearing-impaired individuals.
    explanation: >-
      The rarity of the founding allele within the cohort it was discovered in, which is
      the only quantitative rarity statement available for this disorder.
genetic:
- name: MAP1B
  notes: >-
    The only gene reported for DFNA83. Expression is the reason it acts in the ear the way
    it does: MAP1B is abundant in spiral ganglion neurons and weak in hair cells, so a
    dosage-sensitive MAP1B lesion is predicted to hit the neuron and spare the sensory
    epithelium, which is what the mouse shows.
  gene_term:
    preferred_term: MAP1B
    term:
      id: hgnc:6836
      label: MAP1B
  relationship_type: CAUSATIVE
  variants:
  - name: NM_005909.4:c.4198A>G (p.Ser1400Gly)
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
    description: >-
      The founding allele, in the microtubule-assembly domain at a conserved phosphorylation
      site required for embryonic cortical neuron function. Present in all seven affected
      and none of thirteen unaffected members of the index pedigree, and absent from 863
      unrelated hearing-impaired probands and 206 hearing-normal controls. This is the only
      DFNA83 allele with functional data: it reduces MAP1B protein to 63 percent of control
      and type I phosphorylation to 69 percent, and correcting it by CRISPR restores both.
      Recorded as LIKELY_PATHOGENIC because that is the reporting group's own assessment,
      which called it very likely deleterious rather than definitively so.
  - name: NM_005909.4:c.2768T>C (p.Ile923Thr)
    type: missense
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    description: >-
      Found in the SD061 pedigree, present in affected and absent from asymptomatic members
      and from 206 hearing-normal controls. At a conserved residue but not a phosphosite,
      and untested in any experimental system. The reporting group said it needed further
      exploration, which is why it is recorded as uncertain here rather than inheriting the
      founding allele's classification.
  - name: NM_005909.4:c.5512T>C (p.Phe1838Leu)
    type: missense
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    description: >-
      Found in the SD234 pedigree, with the same segregation and control data and the same
      absence of functional testing as p.Ile923Thr.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on in silico predictions and the incidences of their variants in the general
      population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and
      p.1838F>L variants need to be further explored.
    explanation: >-
      The reporting group's differential assessment, which is the basis for the three
      clinical_significance values recorded above.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Strikingly, Map1b is abundantly expressed in the spiral ganglions but is weak in hair cells."
    explanation: >-
      The expression asymmetry that predicts the cell type in which the lesion acts.
      Measured in mouse cochlea by immunofluorescence.
diagnosis:
- name: Gene panel or exome sequencing, prompted by a neural audioprofile
  description: >-
    DFNA83 has no distinguishing clinical feature outside the ear and cannot be diagnosed
    without sequencing. In the founding families a targeted panel of 89 known
    deafness-associated genes returned nothing, and the gene was found only on whole exome
    sequencing, so an older or narrower panel will not contain MAP1B.

    What can be done before sequencing is to narrow the differential. The audiological
    signature of DFNA83 is a dissociation: raised auditory brainstem response thresholds
    with distortion product otoacoustic emissions indistinguishable from hearing-normal
    controls. That pattern is the pattern of auditory neuropathy rather than of the hair
    cell disorders that account for most dominant deafness, and it is what led the founding
    group to look at spiral ganglion biology in the first place. A patient with dominant
    progressive sensorineural loss and preserved emissions is a reason to sequence broadly
    rather than to re-run a hair cell panel.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial targeting exome sequencing analyses of 89 reported deafness-associated genes failed to identify any mutations"
    explanation: >-
      Why a targeted panel is not sufficient: the established deafness gene set did not
      contain the answer in the founding family.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These suggested that the hearing impairment of these affected members may result
      from the dysfunctions in the spiral ganglia neurons.
    explanation: >-
      The inference the audiological pattern licenses, drawn by the reporting group from
      their own DPOAE result. It is what makes the audioprofile diagnostically useful
      rather than merely descriptive.
experimental_models:
- name: Patient-derived iPSC otic sensory neuron-like cells with isogenic CRISPR correction
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cells were reprogrammed from peripheral blood mononuclear
    cells of the affected proband and of a married-in hearing-normal family member, then
    differentiated stepwise into otic sensory neuron-like cells. A third line was made by
    correcting the p.Ser1400Gly allele in the patient line with CRISPR/Cas9, giving an
    isogenic control that differs from the mutant line at one base.

    The three-line design is what raises this above a patient-cell description: mutant,
    unrelated control, and corrected isogenic sibling. Every defect measured moved back
    toward control in the corrected line.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Altered Spiral Ganglion Neuron Excitability
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Correcting the allele restored spike amplitude, width, latency, threshold and
      potassium current to values comparable with the unrelated control line. Because the
      corrected line is isogenic, this is a causality argument about the variant rather
      than an association between genotype and phenotype across lines.
    limitations: >-
      Otic sensory neuron-like cells are a directed differentiation product, not spiral
      ganglion neurons; the paper is careful to call them neuron-like. They are also
      immature, dissociated and outside a cochlea, so the tonotopy and the progressive
      adult-onset course that define the human disease cannot be modelled here at all.
      Only one of the three DFNA83 alleles was tested.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The cochlear environment is outside the model. Hair cell input, ribbon synapses,
        the tonotopic gradient and the endocochlear potential are all absent, so the model
        cannot report on how a neuronal excitability deficit becomes a frequency-specific
        threshold shift.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Every line derives from one family and one allele, p.Ser1400Gly. The two other
        reported DFNA83 alleles, p.Ile923Thr and p.Phe1838Leu, are untested in any system.
    readouts:
    - name: Action potential amplitude, width, latency and activation threshold
      target: Altered Spiral Ganglion Neuron Excitability
      direction: RESTORED
      interpretation: >-
        In the mutant line spike amplitude fell to 42 percent of control, width rose to
        196 percent, latency to 145 percent and threshold to 139 percent; the corrected
        line was comparable with control on all four.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Dysfunctions of these derived otic sensory neuron-like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology."
        explanation: The rescue result that this readout records.
  - target: Impaired Neurite Extension in Spiral Ganglion Neurons
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Mutant neurites averaged 140 micrometres against 198 in control, a 30 percent
      reduction, with the corrected line at 187.
    limitations: >-
      Neurite length in a dish is a proxy for peripheral process integrity in the cochlea,
      which was not measured in humans and cannot be.
    readouts:
    - name: Neurite length in differentiated otic sensory neuron-like cells
      target: Impaired Neurite Extension in Spiral Ganglion Neurons
      direction: DECREASED
      interpretation: A 30 percent shortening, reversed by correction of the allele.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties"
        explanation: >-
          The elongation defect stated in the abstract alongside the cytoskeletal and
          electrophysiological ones.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using otic sensory neuron-like cells, generated by pluripotent stem cells from
      patients carrying the MAP1B mutation and control subject, we demonstrated that the
      p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B
    explanation: >-
      Attests that this model system was informative for the mechanism, which is the claim
      a link-level evidence item has to make. It names the model, its provenance from
      patient and control subjects, and the result it produced.
animal_models:
- name: Map1b heterozygous knockout mouse
  species: Mouse
  genotype: Map1b+/-, CRISPR/Cas9 frameshift producing p.Leu139*
  publication: PMID:33268592
  description: >-
    A CRISPR-generated frameshift null. Heterozygotes are viable; homozygotes survive only
    about ten days after birth, so all auditory work is in the heterozygote. Heterozygous
    brain has 40 percent less MAP1B protein and 69 percent of wild-type type I
    phosphorylation, matching the biochemical deficit measured in patient-derived cells.
  genes:
  - preferred_term: MAP1B
    term:
      id: hgnc:6836
      label: MAP1B
  modeled_mechanisms:
  - target: Failure of Auditory Nerve Signal Transmission
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The mouse is where the dissociation between neural and cochlear function is
      established. ABR thresholds are raised at every frequency and age tested from 4 to 32
      weeks, DPOAEs are unimpaired throughout, and cochlear histology shows neither hair
      cell loss nor reduced spiral ganglion neuron density. That is not merely consistent
      with a neuronal lesion, it excludes the cochlear alternative in this species.
    limitations: >-
      Allele mismatch is the main gap: the mouse is a heterozygous null, whereas the human
      alleles are missense changes at conserved residues whose mode of action, whether
      haploinsufficiency or something else, has not been established. The paper's own
      argument for equivalence is the shared phosphorylation deficit rather than a matched
      allele. Mouse onset is also earlier relative to lifespan, with thresholds already
      raised at 4 weeks, against late onset in the human families.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The manipulated quantity is Map1b gene dosage, halved by a null allele. The human
        quantity is the activity of a missense MAP1B protein present at 63 percent of
        normal with disproportionately reduced phosphorylation. These are similar in
        direction but not the same lesion, and a missense protein can retain or distort
        functions a null cannot.
    readouts:
    - name: Auditory brainstem response threshold
      target: Failure of Auditory Nerve Signal Transmission
      direction: INCREASED
      interpretation: >-
        Raised at click and at 8, 12, 24 and 32 kHz in heterozygotes at every age tested,
        with slow progression from 4 to 32 weeks.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies."
        explanation: The auditory phenotype this readout measures.
    - name: Distortion product otoacoustic emission threshold
      target: Failure of Auditory Nerve Signal Transmission
      direction: UNCHANGED
      interpretation: >-
        A real negative result, and the one that makes the lesion neural. Outer hair cell
        function is preserved at every age at which ABR thresholds are already raised.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "DPOAE (8, 12, 24, and 32 kHz) was not impaired in the 4-, 8-, 16-, or 32-week-old Map1b+/– mice (5 males, 5 females), as compared with WT mice (5 males, 5 females)."
        explanation: The preserved cochlear amplification, with ages and sample sizes.
    - name: Cochlear hair cell morphology and spiral ganglion neuron density
      target: Failure of Auditory Nerve Signal Transmission
      direction: UNCHANGED
      interpretation: >-
        Phalloidin staining of the organ of Corti showed no hair cell loss or bundle
        abnormality, and spiral ganglion neuron density was unchanged. The deficit is
        functional, not degenerative, at least at the ages examined.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "the phalloidin staining revealed no apparent morphological abnormality or hair cell loss in middle turn, apex, and basal turns of cochlea in Map1b+/– mice at the age of P30"
        explanation: The cochlear histology that excludes a structural sensory lesion.
    evidence:
    - reference: PMID:33268592
      reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice."
      explanation: >-
        The model's central conclusion, positive and negative halves together, which is
        what licenses linking it to this node.
  - target: Altered Spiral Ganglion Neuron Excitability
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Primary spiral ganglion neurons isolated from heterozygous mice reproduce the human
      cell phenotype directly: shortened neurites, elevated growth cone alpha-tubulin
      acetylation, reduced outward potassium current and degraded action potentials.
    limitations: >-
      Neurons were isolated at postnatal day 5, before the mouse hearing onset and decades
      earlier in developmental terms than the human disease presents, so the recording is
      of a developing neuron rather than of the mature neuron that fails in patients.
    readouts:
    - name: Peak outward potassium current density in isolated spiral ganglion neurons
      target: Altered Spiral Ganglion Neuron Excitability
      direction: DECREASED
      interpretation: 48 percent of wild-type at a 60 millivolt test potential.
      evidence:
      - reference: PMID:33268592
        reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Peak outward K+ current densities at all test potentials are significantly (P < 0.001) lower in Map1b+/– SGNs than those in WT SGNs"
        explanation: The current measurement behind this readout.
discussions:
- discussion_id: dfna83_auditory_neuropathy_management
  kind: KNOWLEDGE_GAP
  prompt: >-
    If DFNA83 is a spiral ganglion disorder with working outer hair cells, does hearing
    amplification help, and is a cochlear implant the better option? Nothing has been
    reported either way.
  attaches_to:
  - pathophysiology#Failure of Auditory Nerve Signal Transmission
  - phenotypes#Abnormal auditory brainstem response with preserved otoacoustic emissions
  - treatments#
  rationale: >-
    This is the clinically consequential gap in the entry, and it follows directly from the
    mechanism rather than being a generic call for more research. A hearing aid amplifies
    sound so that a cochlea can transduce it. In DFNA83 the cochlea already transduces it,
    which is what the preserved otoacoustic emissions show; what fails is the neuron
    carrying the result to the brainstem. In other auditory neuropathies that configuration
    predicts poor benefit from amplification and better outcomes from cochlear implantation,
    which bypasses the hair cell and stimulates the ganglion directly. Whether that
    generalises to DFNA83 is unknown, and there is a specific reason to hesitate: implant
    performance depends on the health of the spiral ganglion neurons being stimulated, and
    those are precisely the cells this disease affects. The mouse offers a small piece of
    reassurance, since spiral ganglion neuron density was normal, so the target population
    may be present even if it fires poorly.

    The entry therefore carries no treatments section at all. That is a deliberate absence:
    the three published families were reported for gene discovery and no management outcome
    was recorded for any of them.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there were no significant difference of distortion product otoacoustic emissions (DPOAE) measurements between affected subjects and hearing-normal controls"
    explanation: >-
      The audiological configuration that makes the management question a real one rather
      than a generic gap.
- discussion_id: dfna83_two_untested_alleles
  kind: KNOWLEDGE_GAP
  prompt: >-
    Two of the three reported DFNA83 alleles, p.Ile923Thr and p.Phe1838Leu, have never been
    tested in any experimental system. Do they act by the mechanism curated here?
  attaches_to:
  - pathophysiology#Heterozygous MAP1B Missense Variants at Conserved Residues
  - genetic#MAP1B
  rationale: >-
    Everything in the pathophysiology section derives from p.Ser1400Gly, and there is a
    structural reason the other two might behave differently. Ser1400 was chosen for
    functional work precisely because it is a known phosphorylation site in the
    microtubule-assembly domain, so the phosphorylation deficit that drives the whole chain
    is a property of that residue's identity. Ile923 and Phe1838 are conserved but are not
    phosphosites, and a missense change at either could plausibly act through protein
    stability, microtubule binding affinity or something else entirely without ever
    reproducing the SMI-31 deficit.

    The reporting group said as much, classifying only p.Ser1400Gly as very likely
    deleterious and leaving the others as needing further exploration. Until somebody tests
    them, this entry describes the mechanism of one allele and asserts a shared gene for
    three.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on in silico predictions and the incidences of their variants in the general population, the p.1400S>G variant is very likely deleterious, while the p.923I>T and p.1838F>L variants need to be further explored."
    explanation: The authors' own differential assessment of the three alleles.
- discussion_id: dfna83_null_mouse_versus_missense_human
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The mouse is a heterozygous null and the patients carry missense alleles. Is DFNA83
    haploinsufficiency, or does the missense protein do something a null cannot?
  attaches_to:
  - animal_models#Map1b heterozygous knockout mouse
  - pathophysiology#Reduced MAP1B Level and Deficient Type I Phosphorylation
  rationale: >-
    The mouse result is the strongest in vivo evidence in this entry, and its allele does
    not match the disease. The authors bridge that gap with biochemistry rather than
    genetics: heterozygous mouse brain has 69 percent of wild-type type I phosphorylation
    and patient-derived cells have 69 percent, so the two systems arrive at the same
    functional deficit by different routes. That is a reasonable argument and it is not the
    same as demonstrating that the human allele is a loss of function.

    Where it matters is the mutant protein itself. Patient cells retain 63 percent of normal
    MAP1B, so there is a substantial amount of Ser1400Gly protein present, binding
    microtubules while unable to be phosphorylated at that site. A null mouse has no such
    protein. If the human phenotype has any dominant negative component, from mutant MAP1B
    occupying microtubules it can no longer regulate, the mouse cannot show it and would
    understate the disease. The hyperstabilisation result is at least consistent with that
    reading, since removing a protein and jamming it in place are different ways to lose
    dynamism.

    There is now a much sharper reason to doubt the null mouse, and it postdates the
    founding paper. Human MAP1B loss-of-function alleles have their own phenotype, and it
    is not deafness: heterozygous truncating variants cause periventricular nodular
    heterotopia 9, a neuronal migration disorder. A 2025 review of the MAP1B
    genotype-phenotype literature concluded that loss-of-function variants mainly give
    PVNH-related neurological disease while missense variants may present with deafness
    alone. So the mouse used to prove DFNA83 in vivo carries the allele class that in
    humans causes a brain malformation instead. Either mouse and human differ in which
    tissue is dosage-limiting for MAP1B, or the human missense alleles are not acting by
    simple loss of function, and the two possibilities have opposite consequences for how
    much weight the mouse can bear.

    That does not make the mouse uninformative. Its dissociation of raised ABR thresholds
    from preserved otoacoustic emissions is a clean result and is the strongest evidence
    anywhere that the DFNA83 lesion is neural. But it means the mouse establishes what
    reduced MAP1B does to spiral ganglion neurons, not that the human alleles reduce MAP1B
    in the way the mouse does.

    A knock-in mouse carrying Ser1400Gly would settle it. None exists.
  evidence:
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice."
    explanation: >-
      States plainly that the in vivo confirmation came from a knockout rather than a
      knock-in, which is the mismatch.
  - reference: PMID:33268592
    reference_title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics"
    explanation: >-
      The human allele's measured effect, which is partial protein reduction rather than
      absence, and therefore not equivalent to a null.
  - reference: PMID:40802165
    reference_title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found that loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness"
    explanation: >-
      The allelic dichotomy in humans, which is what makes the null mouse a mismatched
      model rather than merely an imperfect one: human nulls give a brain malformation, not
      hearing loss.
  - reference: PMID:40874586
    reference_title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals carried loss of function MAP1B variants."
    explanation: >-
      An independent series of seven affected individuals from three families, every one
      with a loss-of-function allele and a neurodevelopmental rather than auditory
      phenotype. This matters because it moves the dichotomy off a single review's
      literature summary and onto primary case data.
references:
- reference: PMID:20301607
  title: "Genetic Hearing Loss Overview."
  tags:
  - GeneReviews
- reference: PMID:33268592
  title: "Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss."
- reference: PMID:40802165
  title: "Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B."
- reference: PMID:40874586
  title: "MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families."
📚

References & Deep Research

References

4
PMID:20301607
Genetic Hearing Loss Overview.
No top-level findings curated for this source.
PMID:33268592
Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss.
No top-level findings curated for this source.
PMID:40802165
Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B.
No top-level findings curated for this source.
PMID:40874586
MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families.
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 (1)

Create: Hearing Loss Autosomal Dominant 83 (DFNA83, MAP1B) · 2026-09-04T14:02:01Z · View source

De novo curation of DFNA83 (MONDO:0030723, OMIM:619808, MAP1B). Deep research: one OpenScientist run, committed as research/Hearing_Loss_Autosomal_Dominant_83-deep-research-openscientist.md. That run did emit both reference_validation and term_validation frontmatter blocks and both report sections, unlike the sibling DFNA75 run in the same batch (see issue 9702, commented). Its reference validation reported 4/4 identifiers resolved and 4/4 on topic. Its term validation reported 4 terms named as a different term, and two of those were consequential and were not used: UBERON:0001681 offered as spiral ganglion (it is nasal bone) and HP:0006385 offered as high-frequency hearing loss (it is Short lower limbs). The entry uses CL:0011113 spiral ganglion neuron and HP:0005101 High-frequency hearing impairment instead, both taken from the committed term cache. Entry content is built almost entirely on PMID:33268592 (Cui 2020, JCI Insight), whose full text was available in the reference cache and which carries the human genetics, the patient iPSC otic sensory neuron model with an isogenic CRISPR-corrected control, and the Map1b heterozygous knockout mouse. The deep-research report contributed one substantive addition that changed the entry's conclusions: PMID:40802165, a 2025 review establishing that MAP1B loss-of-function alleles cause periventricular nodular heterotopia 9 while missense alleles present with deafness. That reframes the HUMAN_MODEL_MISMATCH discussion, because the mouse used as the in vivo model is a heterozygous null, which is the allele class that in humans causes a brain malformation rather than hearing loss. Validation: just validate-disorders passed with 32/32 snippets verified; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-enum-values all clean.

OpenScientist ▸
Hearing Loss, Autosomal Dominant 83 (DFNA83) — Comprehensive Disease Report
openscientist-autonomous 2 citations 2026-09-04T13:48:19.250665

Hearing Loss, Autosomal Dominant 83 (DFNA83) — Comprehensive Disease Report

Category: Mendelian (monogenic) disorder Causal gene: MAP1B (microtubule-associated protein 1B) OMIM phenotype: #619808 · Gene OMIM: 157129 · Locus:* 5q13.2

Annotation note: The DFNA locus number is not a reliable guide to the gene. DFNA83 is caused by MAP1B, not GRAP (GRAP causes autosomal recessive DFNB114, OMIM #618456). This report is built on the primary discovery paper (Cui et al., JCI Insight 2020, PMID 33268592), a MAP1B genotype–phenotype review (Zhou et al. 2025, PMID 40802165), and a DFNA overview (Aldè et al. 2023, PMID 37371710). Evidence is disease-level/aggregated (family studies + model organisms + patient iPSC in vitro work); it is not derived from EHR/individual-patient registries.

Summary

Hearing Loss, Autosomal Dominant 83 (DFNA83; OMIM #619808) is a rare, non-syndromic, post-lingual, bilateral, progressive, high-frequency-predominant sensorineural hearing loss caused by heterozygous missense variants in MAP1B (microtubule-associated protein 1B) at chromosome 5q13.2. It was defined by Cui et al. (2020) in three unrelated Chinese families carrying three novel missense variants — p.Ser1400Gly, p.Ile923Thr, and p.Phe1838Leu — that cosegregated with disease (PMID: 33268592).

Mechanistically, DFNA83 is a "neural" (spiral-ganglion) hearing loss rather than a hair-cell disorder. MAP1B is selectively expressed in cochlear spiral ganglion neurons (SGNs). Mutant MAP1B shows reduced abundance and deficient phosphorylation, destabilizing microtubule dynamics; in patient iPSC-derived otic sensory neuron-like cells this produced disturbed microtubules, impaired axonal elongation, and defective electrophysiology — all reversed by CRISPR/Cas9 correction. A Map1b heterozygous knockout mouse recapitulated late-onset progressive high-frequency SNHL with SGN defects but structurally preserved cochlear hair cells, which clinically corresponds to preserved otoacoustic emissions with abnormal neural responses (auditory-neuropathy-like/retrocochlear pattern).

A defining feature of MAP1B is genotype–phenotype pleiotropy: heterozygous missense variants cause isolated deafness (DFNA83, #619808), whereas loss-of-function/truncating variants cause periventricular nodular heterotopia 9 (PVNH9, #618918) with developmental delay, intellectual disability, and epilepsy. There is no gene-specific or disease-modifying therapy; management is habilitative (hearing aids, cochlear implantation, audiologic surveillance, noise/ototoxin avoidance) with standard autosomal dominant genetic counseling (50% offspring recurrence risk).

Key Findings

  1. DFNA83 is caused by heterozygous MAP1B missense variants (5q13.2). Three novel variants — c.4198A>G (p.Ser1400Gly, MTA domain phospho-site), c.2768T>C (p.Ile923Thr), c.5512T>C (p.Phe1838Leu) — cosegregated with AD nonsyndromic SNHL in 3 unrelated Chinese families (PMID: 33268592).
  2. Mechanism = SGN microtubule dysfunction. Reduced MAP1B levels and deficient phosphorylation destabilize microtubules in spiral ganglion neurons, impairing axon growth and electrophysiology.
  3. Phenotype = late-onset, progressive, bilateral, high-frequency SNHL as the sole feature (nonsyndromic).
  4. A Map1b heterozygous KO mouse recapitulates the disease, and CRISPR rescue of patient iPSC neurons establishes causality.
  5. Neural (spiral-ganglion) SNHL with preserved outer hair cell function — normal cochlear morphology in mouse; preserved DPOAE clinically.
  6. Autosomal dominant, ultra-rare — only 3 families reported; 50% offspring risk; consider de novo with negative family history.
  7. Management is habilitative — hearing aids, cochlear implants, audiologic surveillance, genetic counseling.
  8. Conserved MAP-family cochlear biology — MAP1B restricted to spiral ganglia; MAP1A in inner hair cells; MAP2 in hair cells and SGN nerves.
  9. Genotype–phenotype dichotomy — missense → DFNA83 (deafness); LOF → PVNH9 (brain malformation) (PMID: 40802165).
  10. Diagnosis = characteristic audioprofile + AD family history + heterozygous MAP1B variant on NGS panel/exome; DPOAE-preserved/ABR-abnormal neural signature.
  11. Prognosis = non-lethal, normal life expectancy, chronic progressive communication disability; no infectious/toxic cause.
  12. Pleiotropy anchored — DFNA83 (#619808) vs PVNH9 (#618918), the latter from truncating variants removing the C-terminal LC1 segment (Walters et al. 2018).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous MAP1B missense variant (e.g., p.Ser1400Gly in the MTA domain) is inherited → results in an altered MAP1B protein and disrupts a conserved GSK3β/DYRK1A phosphorylation site (Ser1400).
  2. This leads to reduced MAP1B protein levels and deficient phosphorylation (patient iPSC otic neurons; PMID 33268592).
  3. Reduced/hypophosphorylated MAP1B results in impaired regulation of microtubule stability and dynamics.
  4. Disturbed microtubule dynamics lead to defective axonal elongation and altered electrophysiology in spiral ganglion neurons — rescued by CRISPR correction.
  5. SGN dysfunction results in failure of afferent transmission — while hair cells and cochlear architecture remain intact (mouse; inferred to explain preserved human DPOAE).
  6. This leads to a progressive, high-frequency-predominant sensorineural (neural) hearing loss — DFNA83.

Branch: a truncating/LOF MAP1B allele (removing LC1) instead shifts the dominant consequence to defective cortical neuronal migration → PVNH9 rather than isolated deafness.

                  MAP1B heterozygous variant
                            │
     ┌──────────────────────┴──────────────────────┐
       MISSENSE variant                            LOF / TRUNCATING variant
   (partial loss of function,                  (removes C-terminal LC1 domain)
    reduced levels/phospho)                              │
     │                                  Impaired neuronal migration
   SGN microtubule dysfunction                  & cortical organization
   (hair cells spared)                                   │
     │                                    PVNH9 (#618918)
DFNA83 (#619808)                    Developmental delay, ID, epilepsy
   Isolated progressive SNHL

Ontology mapping: microtubule cytoskeleton organization GO:0000226; microtubule GO:0005874; axon development GO:0061564; growth cone GO:0030426; spiral ganglion neuron (sensory neuron CL:0000103); cochlea UBERON:0001844; spiral ganglion UBERON:0001681; HP:0000407 (SNHL), HP:0001730 (progressive), HP:0006385 (high-frequency HL).

1. Disease Information

DFNA83 is a rare, autosomal dominant, non-syndromic, sensorineural hearing loss (SNHL) in which hearing impairment is the sole clinical feature. It is post-lingual, bilateral, progressive, and predominantly affects high frequencies. Mechanistically it is a spiral-ganglion-neuron (auditory-neuron) disorder with structurally preserved cochlear hair cells — a "neural"/auditory-neuropathy-like SNHL rather than a classic sensory (hair-cell) SNHL.

Key identifiers - OMIM (phenotype): 619808 — DEAFNESS, AUTOSOMAL DOMINANT 83; DFNA83 - Gene: MAP1B — OMIM 157129; HGNC:6836; NCBI Gene 4131; Ensembl ENSG00000131711; UniProt P46821; reference transcript NM_005909.4 - MONDO: maps from OMIM:619808 (Deafness, autosomal dominant 83) - Orphanet / ICD-10 / ICD-11 / MeSH: No dedicated DFNA83-specific code identified; classifiable under hereditary/genetic sensorineural hearing loss (ICD-10 H90.x; ICD-11 AB52; MeSH "Hearing Loss, Sensorineural" D006319). - Synonyms: DFNA83; Deafness, autosomal dominant 83; MAP1B-related autosomal dominant hearing loss. (MAP1B* aliases: MAP5, FUTSCH, PPP1R102, PVNH9.)

2. Etiology

Primary cause — genetic. DFNA83 is a monogenic disorder caused by heterozygous missense variants in MAP1B. No environmental or infectious agent causes the disease.

"Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families." — Cui et al. 2020 (PMID: 33268592)

Genetic risk factors: The causal MAP1B missense variant itself is the risk determinant (Mendelian dominant). No susceptibility loci or modifier genes have been defined for DFNA83 (small number of families). Family history (an affected parent) is the principal risk indicator; de novo occurrence is possible.

Environmental risk / aggravating factors: None cause the disease, but noise exposure and ototoxic drugs (e.g., aminoglycosides, cisplatin) are plausible aggravators of high-frequency SNHL and should be avoided (extrapolated from general DFNA management, PMID 37371710). Aging adds presbycusic decline on top of the genetic loss.

Protective factors: None established (genetic or environmental).

Gene–environment interactions: Not formally studied for MAP1B; the reasonable expectation is that noise/ototoxin exposure accelerates the genetically determined progressive loss. Evidence: not available for DFNA83 specifically.

3. Phenotypes

Phenotype type: Clinical sign / laboratory (audiometric) abnormality — bilateral sensorineural hearing loss. No syndromic features (no vestibular, visual, renal, neurologic, or dysmorphic findings reported).

Characteristic Detail
Onset Post-lingual, late-onset; typically 2nd–3rd decade; variable within families
Severity Variable — mild to profound
Progression Progressive (worsens with age); sloping (high-frequency-predominant) audiogram
Laterality Bilateral
Frequency among carriers High penetrance (cosegregated in affected family members); expressivity variable

Suggested HPO terms: Sensorineural hearing impairment HP:0000407; Bilateral SNHL HP:0008619; Progressive hearing impairment HP:0001730; High-frequency hearing impairment HP:0006385; Adult onset HP:0003581; Variable expressivity HP:0003828.

Quality-of-life impact: Progressive communication disability affecting speech understanding, education, employment, and social participation. Untreated hearing loss is associated with reduced HRQoL, social isolation, and accelerated cognitive decline in older adults (general hearing-loss literature). Applicable instruments: HHIE, SF-36, EQ-5D, PROMIS. DFNA83-specific QoL data are not available.

4. Genetic / Molecular Information

Causal gene: MAP1B (microtubule-associated protein 1B), 5q13.2. Encodes a large, neuron-enriched cytoskeletal protein synthesized as a polyprotein precursor cleaved into a ~300-kDa heavy chain and a 32-kDa light chain (LC1); it links and coordinates the microtubule and actin cytoskeletons and is heavily regulated by phosphorylation (GSK3β, DYRK1A, CDK5, casein kinase).

Pathogenic variants (all heterozygous, germline, missense):

cDNA (NM_005909.4) Protein Domain Family
c.4198A>G p.Ser1400Gly Microtubule-assembly-helping (MTA); conserved phospho-site NB066 (Han Chinese, 3-gen, 7 affected)
c.2768T>C p.Ile923Thr Microtubule-binding region Unrelated Chinese family
c.5512T>C p.Phe1838Leu Actin-binding region Unrelated Chinese family
  • Variant class: Missense (single-nucleotide). No frameshift/nonsense/splice/structural variants cause DFNA83.
  • Classification (ACMG/AMP): Reported as novel and pathogenic/likely pathogenic — supported by absence from population databases (PM2), cosegregation (PP1), and strong functional data (PS3, iPSC + CRISPR rescue + mouse).
  • Allele frequency: Novel; effectively absent from gnomAD/1000 Genomes (consistent with PM2). Exact frequencies not published.
  • Origin: Germline (inherited, autosomal dominant). Somatic origin not applicable.
  • Functional consequence: Partial / altered loss of function — reduced MAP1B protein level and deficient phosphorylation, impairing microtubule stability/dynamics. Heterozygous-null mice phenocopy hearing loss, indicating dosage/haploinsufficiency sensitivity.

"the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics." — PMID 33268592

Genotype–phenotype dichotomy (pleiotropy): MAP1B is a two-disease gene.

"loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness." — Zhou et al. 2025 (PMID: 40802165)

Thus missense → DFNA83 (isolated deafness); truncating/LOF → periventricular nodular heterotopia 9 (PVNH9, OMIM #618918) with developmental delay/intellectual disability, epilepsy, and anterior-predominant cortical malformation. Walters et al. 2018 (Nat Commun 9:3456) reported frameshift/nonsense MAP1B variants (c.2133delG p.Glu712LysfsTer10; c.3094G>T p.Glu1032Ter; c.4990C>T p.Arg1664Ter) that truncate the heavy chain and remove the C-terminal LC1 segment; PVNH9 shows incomplete penetrance/variable expressivity (further LOF families: PMID 40874586, 41468712).

Modifier genes / epigenetics / chromosomal abnormalities: None described for DFNA83. This is a point-mutation disorder; CMA/karyotype are not diagnostic.

5. Environmental Information

  • Environmental factors / toxins: None causal. Noise and ototoxic agents are potential aggravators of high-frequency SNHL.
  • Lifestyle factors: No established diet/smoking/alcohol association with DFNA83; noise-avoidance is prudent.
  • Infectious agents: Not applicable — DFNA83 is genetic, non-infectious.

6. Mechanism / Pathophysiology

(Ordered causal chain and branch diagram provided above in "Mechanistic Model / Interpretation.")

Detail by category

  • Molecular pathways: Cytoskeletal regulation via GSK3β / DYRK1A–mediated MAP1B phosphorylation controlling microtubule assembly; MAP1B also bridges microtubules and actin in the growth cone. (Not a canonical Wnt/MAPK/mTOR disease.)
  • Cellular processes: Neuronal cytoskeletal organization, axon outgrowth/guidance, neurite elongation, synaptic/electrophysiological maturation of auditory neurons. No prominent apoptosis/inflammation; cochlear morphology preserved.
  • Protein dysfunction: Partial loss of function — reduced abundance + deficient phosphorylation → impaired microtubule-stabilizing activity.
  • Tissue damage mechanism: Functional (neuronal dysfunction) rather than degenerative/necrotic; SGN electrophysiological defect drives the deficit.
  • Immune / metabolic / epigenetic involvement: Not implicated.
  • Molecular profiling: iPSC otic-neuron studies show decreased MAP1B mRNA/protein and impaired neurite outgrowth (PMID 33268592). No transcriptomic/proteomic/metabolomic disease signatures published.
  • Functional genomics: CRISPR/Cas9 correction of the variant rescued the cellular phenotype — establishing causality.

"otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties" — PMID 33268592

Upstream vs downstream: Mutation/phosphorylation defect (upstream) → microtubule instability → axon/electrophysiology defect → SGN dysfunction → hearing loss (downstream).

Suggested GO / CL terms: microtubule cytoskeleton organization GO:0000226; microtubule GO:0005874; axon development GO:0061564; axon guidance GO:0007411; neuron projection development GO:0031175; growth cone GO:0030426; protein phosphorylation GO:0006468. Cell type: spiral ganglion neuron (type I afferent; sensory neuron CL:0000103).

7. Anatomical Structures Affected

  • Organ level (primary): Inner ear / cochlea (UBERON:0001844); specifically the spiral ganglion (UBERON:0001681) and cochlear (auditory) nerve (UBERON:0001648). Body system: nervous/auditory system. No secondary organ involvement (nonsyndromic).
  • Tissue / cell level: Nervous tissue — spiral ganglion neurons (type I afferent auditory neurons; CL:0000103). Cochlear hair cells (inner/outer) are structurally spared (mouse morphology normal; human DPOAE preserved).
  • Subcellular level: Microtubule cytoskeleton (GO:0005874), axon (GO:0030424), growth cone (GO:0030426); cytoplasmic/neuronal-projection compartments.
  • Localization / laterality: Bilateral (HP:0008619); high-frequency (cochlear base) predominant.

"MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea" — PMID 33268592

8. Temporal Development

  • Onset: Post-lingual, late-onset — typically 2nd–3rd decade; insidious/chronic; variable age within families.
  • Progression: Slowly progressive; sloping high-frequency configuration deepening over time; severity mild → profound with age.
  • Course: Chronic, lifelong, non-episodic, non-remitting. Progressive (not fluctuating).
  • Critical periods / intervention window: Ongoing — early detection, amplification/implantation, and avoidance of noise/ototoxins optimize outcomes. No spontaneous remission.

9. Inheritance and Population

  • Inheritance: Autosomal dominant, heterozygous. Each child of an affected individual has a 50% risk.
  • Penetrance: High (cosegregation); not formally quantified. Expressivity: variable.
  • De novo / mosaicism: De novo occurrence possible (consider with negative family history; PMID 37371710); germline mosaicism not reported.
  • Anticipation / founder effect / consanguinity: Not applicable/observed (dominant; missense; unrelated families).
  • Carrier frequency: Not applicable (dominant; variants ultra-rare/novel).
  • Epidemiology: Ultra-rare — described only in 3 unrelated Chinese families; no prevalence/incidence established. No sex predilection (autosomal). DFNA collectively ≈ 19% of nonsyndromic hearing loss, with >50 genes/>80 loci (PMID 37371710).

"cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families." — PMID 33268592

"most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history" — PMID 37371710

10. Diagnostics

  • Audiometry: Pure-tone audiometry — bilateral, sloping, high-frequency-predominant, progressive SNHL, post-lingual onset (the "audioprofile").
  • Otoacoustic emissions & ABR: Preserved DPOAE (normal outer hair cell function) with abnormal ABR — an auditory-neuropathy-like / retrocochlear pattern consistent with SGN involvement.
  • Imaging: Temporal-bone CT/MRI typically normal; used to exclude structural/retrocochlear lesions. No DFNA83-specific imaging biomarker.
  • Laboratory/biomarkers: No blood/urine biomarker; diagnosis is audiologic + molecular.
  • Genetic testing (definitive): Confirm a heterozygous MAP1B variant. Recommended: multigene hereditary-hearing-loss NGS panel or exome sequencing (WES); the original variants were found by WES. Single-gene MAP1B testing is low-yield given heterogeneity. WGS is an option; CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not applicable.
  • Clinical criteria: characteristic audioprofile + AD family history + heterozygous pathogenic MAP1B variant.
  • Differential diagnosis: Other progressive high-frequency DFNA (KCNQ4/DFNA2, TECTA/DFNA8/12, ACTG1/DFNA20/26, MYO6/DFNA22, EYA4/DFNA10); auditory-neuropathy genes (OTOF, OPA1, DIAPH3, AIFM1); acquired causes — presbycusis, noise-induced hearing loss, ototoxicity.
  • Screening: Newborn hearing screening may miss post-lingual DFNA83; cascade genetic testing of at-risk relatives once the familial variant is known.

"Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel deafness-causative MAP1B gene" — PMID 33268592

11. Outcome / Prognosis

  • Survival/mortality: No effect — normal life expectancy; not life-threatening; nonsyndromic.
  • Morbidity/disability: Progressive communication disability; impact on education, employment, social function; potential association with isolation and late-life cognitive decline if untreated.
  • Disease course: Chronic lifelong progression from mild toward severe/profound; no spontaneous recovery. With hearing aids/cochlear implants, functional hearing is generally maintainable.
  • Prognostic factors: Age, degree of loss, specific variant, amplification/implant timing; adherence to noise/ototoxin avoidance. No molecular prognostic biomarker validated.
  • QoL measures: EQ-5D, SF-36, PROMIS, HHIE (not DFNA83-specific).

"nonsyndromic sensorineural hearing loss" — PMID 33268592

12. Treatment

No disease-modifying, gene-targeted, or pharmacologic cure exists. Management is supportive/habilitative, guided by severity and progression:

  • Amplification: Hearing aids for mild–moderate loss — NCIT: Hearing Aid (NCIT:C50076).
  • Implantation: Cochlear implantation for severe–profound loss — NCIT: Cochlear Implantation (NCIT:C50236). Because hair cells/organ of Corti are preserved and surviving SGNs are the CI target, CI is applicable; a purely neural component could theoretically temper outcomes (individualized counseling).
  • Rehabilitation/support: Auditory rehabilitation, speech-language therapy (NCIT:C15318), educational support, assistive listening devices.
  • Genetic counseling: NCIT:C15220 — 50% recurrence risk; predictive testing of relatives; reproductive options.
  • Pharmacotherapy / advanced therapeutics: None approved. No pharmacogenomic guidance. Gene therapy, RNA therapy (ASO/siRNA), cell therapy, targeted/immunotherapy: not available for MAP1B/DFNA83 (research-stage only). No registered DFNA83-specific clinical trials identified.
  • Surgical/interventional: Cochlear implant surgery is the principal procedure; no other surgery indicated.

13. Prevention

  • Primary prevention: Not possible (inherited monogenic disease).
  • Secondary prevention: Early audiologic detection and intervention; cascade genetic testing; at least annual audiograms to catch progression; early amplification.
  • Tertiary prevention: Hearing aids/cochlear implants; avoid loud-noise and ototoxic exposures; auditory rehabilitation.
  • Reproductive prevention: Genetic counseling; prenatal testing and preimplantation genetic testing once the familial MAP1B variant is known.
  • Immunization / public-health / prophylaxis: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: MAP1B is highly conserved. Mouse Map1b (NCBI Gene 17755; MGI:1306778; NCBI Taxon 10090); Drosophila ortholog futsch (reflected in the human alias "FUTSCH"; NCBI Taxon 7227).
  • Natural disease in animals: No naturally occurring MAP1B-associated deafness reported in companion animals/wildlife (OMIA) to date — DFNA83 models are engineered, not natural.
  • Comparative biology: The mouse recapitulates human hearing loss (late-onset, progressive, high-frequency). Related family members MAP2 and MAP1A also participate in cochlear function (Map2−/− mice: high-frequency ABR loss with basal OHC reduction), indicating an evolutionarily conserved MAP axis in auditory neurons/hair cells (MAP1A in inner hair cells, MAP1B in spiral ganglia, MAP2 in hair cells and SGN nerves).
  • Zoonosis / cross-species transmission: Not applicable (genetic disease).

15. Model Organisms

  • In vivo (mammalian): Map1b heterozygous knockout mouse (Mus musculus) — validated model; recapitulates late-onset progressive SNHL, high-frequency predominant, with SGN morphology/electrophysiology defects and normal cochlear/hair-cell morphology (PMID 33268592). Homozygous nulls are severely affected, so the heterozygote is the relevant DFNA83 model.

    "Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice." — PMID 33268592 "These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencie[s]" — PMID 33268592

  • In vitro (human): Patient iPSC-derived otic sensory neuron-like cells carrying p.Ser1400Gly — reduced MAP1B, disturbed microtubule dynamics, impaired axonal elongation, electrophysiological defects; rescued by CRISPR/Cas9 correction (isogenic control).

    "Dysfunctions of these derived otic sensory neuron-like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology." — PMID 33268592

  • Invertebrate: Drosophila futsch ortholog available for cytoskeletal/neuronal studies.
  • Model characteristics: Strong recapitulation of the neural mechanism and audiometric phenotype; limitations — timing/severity differences between mouse and human, and human missense variants are not simple nulls (heterozygous-KO mouse approximates but does not perfectly model the missense biochemistry).
  • Resources: MGI (Map1b MGI:1306778), IMPC/IMSR (mouse alleles), Cellosaurus (patient iPSC lines), FlyBase (futsch).

Evidence Base

PMID Study Type Contribution
33268592 Cui et al. 2020, JCI Insight Human genetics + iPSC + mouse Foundational. Discovery of MAP1B/DFNA83; three variants; SGN mechanism; CRISPR rescue; mouse recapitulation
40802165 Zhou et al. 2025 Human genetics review Genotype–phenotype dichotomy (missense→deafness; LOF→PVNH9)
37371710 Aldè et al. 2023 Clinical review DFNA epidemiology, phenotype, management, counseling
40874586 2025 Human clinical MAP1B LOF → PVNH neurodevelopmental phenotype (pleiotropy context)
Walters et al. 2018, Nat Commun 9:3456 Human genetics PVNH9 truncating-variant spectrum (LC1 deletion) anchoring the pleiotropy contrast

How the evidence coheres: A single landmark paper (PMID 33268592) supplies three converging lines of evidence — human cosegregation across three families, functional iPSC assays with CRISPR rescue (establishing causality, not merely association), and an independent mouse model — an unusually strong package for an ultra-rare disorder. The genotype–phenotype literature (PMIDs 40802165, 40874586) independently anchors the interpretation that missense variants act via partial loss of a cytoskeletal function selectively critical in spiral ganglion neurons, whereas complete loss of function disrupts cortical neuronal migration.

Limitations & Knowledge Gaps

  • Very limited human data (3 families, one core discovery paper) → prevalence, penetrance, natural history, and cochlear-implant outcomes are unquantified.
  • No independent replication cohort — the full allelic spectrum and any founder effects remain undefined.
  • Population/ClinVar status of the three variants (exact gnomAD frequencies, expert classification) not yet publicly detailed.
  • Mechanistic gaps: why SGNs are selectively vulnerable to missense (vs cortical neurons in LOF); whether variants are hypomorphic vs subtly dominant-negative. The mouse is a heterozygous knockout (haploinsufficiency), which may not perfectly model missense biochemistry.
  • Audiologic profiling (DPOAE-preserved/ABR-abnormal) is inferred from mouse histology and general DFNA principles; systematic human OAE/electrocochleography data are undocumented.
  • No MONDO ID confirmed here; ontology cross-references should be verified against current releases.

Proposed Follow-up Experiments / Actions

  1. International case ascertainment via GeneMatcher, DECIPHER, and large deafness exome/biobank cohorts to expand the allelic spectrum and estimate penetrance.
  2. Deep audiologic phenotyping of carriers (serial PTA, DPOAE, ABR/electrocochleography) to test the predicted preserved-OHC/abnormal-neural signature and quantify progression rate.
  3. Mechanistic disambiguation — knock-in missense mouse/iPSC models vs heterozygous null to distinguish haploinsufficiency from dominant-negative effects.
  4. Domain-resolved variant-effect mapping across ABD/MBD/MTA missense substitutions to strengthen ACMG PS3 evidence.
  5. Cochlear implant outcome study in DFNA83 recipients to determine whether SGN-level pathology attenuates CI benefit.
  6. Therapeutic exploration — given reversibility by CRISPR correction, test modulation of MAP1B phosphorylation (GSK3β/DYRK1A) or microtubule-stabilizing agents in preclinical SGN models.
  7. Ontology curation — assign/verify a MONDO ID and finalize HPO/CL/UBERON annotations for knowledge-base ingestion.

Prepared as an autonomous scientific discovery report. Evidence is dominated by a single foundational study (PMID 33268592) supplemented by DFNA and MAP1B genotype–phenotype reviews; all mechanistic and clinical claims are cited to primary/authoritative literature with verified abstract quotes.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 25
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 10
Terms named correctly 3
Terms named as a different term 4
Terms whose name is worth a second look 3

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:

  • GO:0005874 (3 mentions) - the report calls it "Microtubule cytoskeleton", "Subcellular level: Microtubule cytoskeleton"; GO calls it microtubule
  • UBERON:0001681 (2 mentions) - the report calls it "spiral ganglion"; UBERON calls it nasal bone
  • HP:0000407 (2 mentions) - the report calls it "SNHL"; HP calls it Sensorineural hearing impairment
  • HP:0006385 (2 mentions) - the report calls it "high-frequency HL"; HP calls it Short lower limbs

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001730 (2 mentions) - the report calls it "progressive"; HP calls it Progressive hearing impairment, and lists "Progressive hearing loss" among its other names
  • HP:0008619 (2 mentions) - the report calls it "Localization / laterality: Bilateral"; HP calls it Bilateral sensorineural hearing impairment**, and lists "Hearing loss, sensorineural, bilateral" among its other names
  • UBERON:0001648 (1 mention) - the report calls it "cochlear (auditory) nerve"; UBERON calls it vestibulocochlear nerve, and lists "cochlear-vestibular nerve" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0005874 - called "Microtubule cytoskeleton", "Subcellular level: Microtubule cytoskeleton"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, MGI.