Hearing Loss Autosomal Dominant 76

Mendelian MONDO:0032917 Pathograph 11 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA76 is autosomal dominant nonsyndromic sensorineural hearing loss caused by heterozygous variants in PLS1, which encodes plastin 1 (fimbrin) - one of the three actin cross-linkers that build the stereocilium's actin core, and by mass the most abundant of them in vestibular bundles. The mechanism is bundle architecture, not transduction machinery and not synaptic function. Plastin 1 is not needed to build a stereocilium. It is needed to keep one. Knockout mice develop normal hair bundles and then lose them: inner hair cell stereocilia narrow and shorten in young adults, outer hair cells degenerate later, and hearing declines moderately and progressively across all frequencies without early hair cell death. What plastin 1 contributes is width. It biases the actin filaments away from tight hexagonal packing towards a disordered liquid packing, and it is that looser arrangement that lets a stereocilium grow to full diameter. The gap between that mouse and the human disease is the central problem of this entry, and it is not the usual species caveat. The dose question is partly open rather than untouched: Pls1 *heterozygous* nulls shift with age against themselves, hinting at a late and mild deterioration, but they never reach a significant deficit against wild-type controls and they serve as the paper's normal genotype on every structural and transduction measure. So whether one working copy suffices is unsettled in mouse, and whether the human alleles behave like a missing copy at all is untested. Every reported human allele is a missense change in an actin-binding domain or a splice variant producing an in-frame internal deletion - not a truncation, not a whole-gene deletion - so a protein is present in every patient. When the two were compared directly in zebrafish, they behaved oppositely: dye uptake through the mechanotransduction channel was reduced by the mutant protein and increased in the knockout, and neither loss of plastin 1 nor re-expression of wild-type protein reproduced the mutant's defect. The authors conclude a dominant-negative effect with partial loss of function, and are careful to say that they did not co-express wild-type and mutant protein, so the dominant-negative step is inferred from the divergence rather than demonstrated. Clinically the picture is heterogeneous across a handful of families and should not be compressed into one sentence. The Chinese family carrying the exon-skipping allele has progressive, unilateral or bilateral, moderate-to-severe high-frequency loss beginning in childhood; the Turkish family with p.Glu269Lys had symmetric, moderate, postlingually diagnosed progressive loss; a second Chinese family with a nearby splice variant presented with congenital loss that failed newborn screening in the proband and in her mother. Onset therefore spans congenital to adult, and the only defensible summary is that the loss is sensorineural, predominantly high-frequency, and usually progressive once it starts.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Hypotheses
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Gaps
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Pathograph
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Genes
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Medical Actions
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Models
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References
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Deep Research
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Mappings

MONDO
MONDO:0032917 hearing loss, autosomal dominant 76
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous PLS1 variants segregating with hearing loss across generations in independent families of European, Roma, Turkish and Chinese ancestry. No homozygote or compound heterozygote has been reported, and no unaffected carrier has been documented, though penetrance has not been formally estimated in any pedigree.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31397523 SUPPORT Human Clinical
"In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice."
The founding gene-disease conclusion, stating the inheritance mode. Three unrelated dominant pedigrees underlie it, which is what took PLS1 past a single-family observation.
PMID:30872814 SUPPORT Human Clinical
"We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI."
The independent contemporaneous report in a different population, published within months of the founding paper and reaching the same inheritance conclusion.
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Mechanistic Hypotheses

2
Dominant-negative mutant plastin 1 with partial loss of function
dominant_negative_actin_crosslinking_model EMERGING
Evidence balance 1 support 1 no evidence
The mutant protein does something, rather than simply failing to do something. Direct comparison in zebrafish separates the two: the exon-8-skipping mutant reduces FM1-43 dye uptake through the mechanotransduction channel, while knocking plastin 1 out increases it, and neither the knockout nor re-expressed wild-type protein reproduces the mutant's reduction. Biochemically the mutant retains actin binding but binds abnormally, disrupting the intramolecular ABD1-ABD2 interaction that normally restrains the high-affinity domain, and it co-precipitates more ACTG1 than wild-type protein does. This is EMERGING rather than CANONICAL for a reason the authors state themselves: they did not co-express wild-type and mutant plastin 1, which is the experiment a dominant-negative claim requires, so the conclusion is inferred from the functional divergence between knockout and mutant rather than demonstrated in the heterozygous configuration the patients are actually in. It is also based on one allele. The four reported missense alleles have not been through the same analysis, and the modelling that predicted them to destabilise the first actin-binding domain is in silico.
Pathograph links
PLS1 Heterozygous Variant -> Impaired Actin Cross-Linking by Plastin 1 DIRECT
Impaired Actin Cross-Linking by Plastin 1 -> Impaired Mechanoelectrical Transduction INDIRECT UNKNOWN INTERMEDIATES Intermediates: Stiffened and abnormally arranged actin bundles altering the mechanical context of the transduction channel; Altered association of plastin 1 with ACTG1 and MYO1C at the bundle
Impaired Mechanoelectrical Transduction -> Progressive Sensorineural Hearing Impairment DIRECT
Show evidence (2 references)
PMID:41922548 SUPPORT Model Organism
"Notably, neither PLS1 deficiency nor re-expression of human wild-type PLS1 in knockout zebrafish reproduces this MET defect. Thus, the mutation not only reduces native PLS1 function but also interferes with normal MET channel activity."
The observation the whole hypothesis rests on: an effect present with the mutant and absent both from the null and from wild-type rescue, which is what "not simple loss of function" means operationally.
PMID:41922548 NO_EVIDENCE Model Organism
"We did not directly assess the co-expression of wild-type and mutant PLS1, and future studies are needed to confirm the dominant-negative mechanism under physiologically relevant conditions."
Graded NO_EVIDENCE rather than REFUTE: the sentence reports an experiment that was not done. It does not cut against the hypothesis, it is the reason the hypothesis is EMERGING.
Reduced plastin 1 dosage from an unstable mutant protein
haploinsufficiency_model ALTERNATIVE
Evidence balance 4 support 1 refute 1 no evidence
The simpler reading, and one the same study supports in part. The exon-8-skipping protein has a markedly shorter half-life than wild type, is more heavily ubiquitinated, and is degraded within twelve hours where the wild-type protein is stable, so cells carrying it hold less plastin 1 overall. On this model the disease is a dosage problem and the mouse null - moderate, progressive, late-onset loss - is the right model after all. There is a mouse observation that bears on this model and that the dominant-negative framing must not be allowed to obscure - but it is weaker than it first looks, and the same paper contains its counterweight. What is tested and positive: heterozygous nulls shift with age against *themselves*. Wild-type animals show no threshold shift between the youngest and oldest cohorts, and heterozygotes show a significant one. What is *not* established: a deficit against wild-type controls. On click ABR in animals older than six months there was no significant difference between heterozygotes and wild type, and the tone-pip elevation described at seven to nine months carries no statistic - the figure legend marks significance for knockout versus wild type only. The paper also uses heterozygotes as a control genotype throughout its stereocilia morphology, hair cell electrophysiology and transduction measurements, where they behave normally. So the honest reading is that heterozygous nulls plausibly develop a late, mild deterioration, and that halving plastin 1 has never been shown to produce a deficit a properly powered comparison would detect. That is suggestive for dosage sufficiency and it is not settled. Recorded as ALTERNATIVE rather than dismissed because the two are not exclusive and the authors present them side by side: reduced stability accounts for the loss-of-function component, and the divergent transduction phenotype accounts for the rest. What would separate them is a truncating PLS1 allele or a whole-gene deletion in a hearing-impaired person; none has been reported.
Pathograph links
PLS1 Heterozygous Variant -> Impaired Actin Cross-Linking by Plastin 1 DIRECT
Show evidence (6 references)
PMID:41922548 SUPPORT In Vitro
"CHX-chase experiments revealed rapid degradation of ΔExon8-PLS1 within 12 h, whereas WT-PLS1 remained stable, indicating that the mutation substantially reduced protein stability."
The measured instability that gives the dosage model its footing, from a cycloheximide-chase experiment in cells.
PMID:41922548 SUPPORT In Vitro
"Unlike the dominant-negative effects described above, this aspect of the phenotype is more consistent with a dosage-insufficient, partial loss-of-function mechanism."
The authors' own separation of the two arms, which is why this entry carries both as named hypotheses rather than choosing one.
PMID:25124451 SUPPORT Model Organism
"In mice aged 7–9 months, hearing thresholds were elevated for het animals for all frequencies tested between 8 and 32 kHz"
The observation that carries the most weight for this model: a mouse with one functional Pls1 copy and no mutant protein develops hearing loss with age. Halving the dose is sufficient, which is what haploinsufficiency asserts.
+ 3 more references
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Discussions and Knowledge Gaps

2
The main in vivo model of DFNA76 is a homozygous Pls1-null mouse, and the disease is dominant in people carrying one missense or in-frame-deletion allele. Zebrafish data say the null and the human-type mutant perturb mechanotransduction in opposite directions. How much of the mouse phenotype should be read as DFNA76?
HUMAN MODEL MISMATCH pls1_null_mouse_versus_dominant_human_allele
Attached to
animal_models#Pls1 knockout mouse pathophysiology#Impaired Mechanoelectrical Transduction mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
The Pls1-null mouse has earned its place. It predicted, before any patient was found, that human PLS1 mutations would cause relatively mild progressive hearing loss; it is where the maintenance role of plastin 1 was established; and it is the material in which the actin-packing result was obtained. Every structural claim in this entry's pathophysiology depends on it. But it is a null, and DFNA76 is not a null disease. Six alleles have been reported and not one is truncating: four missense changes in or beside the actin-binding domains, and two splice variants at a single donor site that remove an internal segment in frame. A protein is made in every reported patient. When the two situations were compared directly - the only time they have been - they came apart on the measurement that matters most for a mechanosensory cell: dye uptake through the transduction channel fell with the human mutant and rose in the knockout, and wild-type protein re-expressed in the knockout did not reproduce the mutant's defect. So the mouse is a good model of losing plastin 1 and an unknown model of having a defective one. That distinction is not academic. If the dominant-negative reading is right, gene addition - the modality being developed for recessive deafness genes - would add wild-type protein alongside a mutant that is actively interfering, and the therapeutic strategy would have to be allele-specific silencing instead. If the dosage reading is right, augmentation is exactly right. Nothing published distinguishes them, and the experiment that would is not hard: no mouse carrying a human PLS1 missense or exon-skipping allele has been made. A second, quieter mismatch sits underneath. The zebrafish knockout phenotype is modest, and the authors attribute that to espin and fascin partially compensating for absent plastin 1 - so the null arm of the comparison may understate the consequence of losing the protein, which would narrow rather than widen the gap between the two. That possibility has not been tested either.
Proposed experiments
Knock-in mouse allele series for a DFNA76 missense and the exon-skipping allele
exp_dfna76_knockin_mouse_allele_series
Generate mice carrying the recurrent p.Glu269Lys missense allele and the exon-skipping allele in the endogenous Pls1 locus, and phenotype heterozygotes against wild-type, Pls1 heterozygous nulls and Pls1 homozygous nulls with auditory brainstem response and distortion product otoacoustic emissions across ages, scanning electron microscopy of bundle morphology, stereocilium width morphometry, and single-cell transducer current and adaptation recordings. The heterozygous-null arm is the critical comparison and it is the arm that is currently underpowered: existing data show heterozygotes shifting against themselves with age but never reaching a significant deficit against wild type, so this experiment has to settle both questions at once - whether heterozygous nulls are affected at all on an adequately powered comparison, and, if they are, whether knock-in heterozygotes are affected earlier, more severely, or with a transduction phenotype of the opposite sign.
Would support
mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
Would refute
mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
Supporting outcome
  • Knock-in heterozygotes lose hearing while heterozygous nulls do not, or lose it earlier and more severely than nulls of the same age, and their transducer phenotype differs in direction from the null's - either result would establish the dominant-negative mechanism in the heterozygous configuration patients are in and make allele-specific silencing the rational therapeutic target.
Refuting outcome
  • Knock-in heterozygotes and Pls1 heterozygous nulls are indistinguishable in onset, severity and transduction phenotype - both late, mild and progressive - which would make DFNA76 a haploinsufficiency disease, would retire the dominant-negative hypothesis, and would make gene augmentation the appropriate modality.
Show evidence (7 references)
PMID:41922548 SUPPORT Model Organism
"Notably, neither PLS1 deficiency nor re-expression of human wild-type PLS1 in knockout zebrafish reproduces this MET defect. Thus, the mutation not only reduces native PLS1 function but also interferes with normal MET channel activity."
The direct statement of the mismatch, with the wild-type rescue arm as the control.
PMID:41922548 SUPPORT Model Organism
"Because Espin and Fascin are also expressed in zebrafish stereocilia and can partially compensate for the absence of PLS1"
The reason the knockout arm may understate plastin 1 loss, which is the second-order uncertainty inside the comparison.
PMID:41922548 SUPPORT Model Organism
"Therefore, it is essential to define the pathogenic mechanism of each mutation, particularly distinguishing between loss-of-function and dominant-negative mutations."
The authors' framing of why the distinction is a therapeutic question rather than a taxonomic one, stated in the context of AAV gene therapy.
+ 4 more references
DFNA76 onset spans congenital to adult across a handful of families. Is that allele-driven, and can a family carrying a PLS1 variant be told when to expect the loss?
KNOWLEDGE GAP pls1_onset_heterogeneity
Attached to
phenotypes#Congenital Onset in Some Families phenotypes#Progressive Sensorineural Hearing Impairment progression#Onset
The reported families do not agree about when this disease starts. One Chinese family failed newborn screening in two generations. The other Chinese family's loss begins in childhood and progresses. The Turkish p.Glu269Lys family was diagnosed postlingually. That is a wider onset range than most dominant nonsyndromic hearing loss genes show, and it is currently unexplained. Two readings are available and neither has been tested. The alleles may differ in consequence - the splice variants remove an internal segment while the missense changes substitute a single residue, and it would not be surprising if those produced different ages of onset. Or onset may vary within an allele, as it demonstrably does for the unrelated TPRN null in DFNB79, in which case a modifier or an environmental contribution is at work and genotype will never answer the question. Distinguishing them needs no new technology, only aggregation: the published families are individually too small, but pooling their audiograms by allele would show immediately whether the two splice families cluster apart from the missense families. Nobody has done it, and the reason is prosaic - the reports are scattered across four journals in three countries and no DFNA76 registry exists. The counselling stake is concrete. A couple whose child carries a PLS1 variant currently cannot be told whether to expect a failed newborn screen, a school-age diagnosis, or nothing until adulthood, which changes what surveillance to arrange and when.
Show evidence (3 references)
PMID:41822198 SUPPORT Human Clinical
"The proband (III-1), a 7-year-old girl, was diagnosed with congenital hearing loss, failing newborn hearing screening, which included otoacoustic emissions and automatic auditory brainstem response"
The congenital pole of the onset range, objectively documented.
PMID:41922548 SUPPORT Human Clinical
"Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
A childhood-onset progressive course in a family carrying a splice allele at the same donor site as the congenital family's, which is the observation that makes the allele-driven explanation hard to sustain on its own.
PMID:31432506 SUPPORT INDIRECT Human Clinical
"Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL."
The missense family whose postlingual diagnosis is the third point in the onset range. Indirect because the abstract establishes the family and the allele without stating the age of onset, which is reported in the paper's body.
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Pathophysiology

4
PLS1 Heterozygous Variant
A single altered PLS1 allele. The reported spectrum falls into two classes and contains no truncation. Four missense changes sit in or adjacent to the actin-binding regions - p.Phe128Ser, p.Leu238Arg and the recurrent p.Glu269Lys in European and Turkish families, and p.Leu363Phe in the calponin-homology 2 domain in a Hungarian Roma family. Two splice variants at the same donor site, c.981+1G>A and c.981+5G>A, produce an in-frame internal deletion of the region encoded by that exon; the two reports number the skipped exon differently, so this entry names the donor site rather than an exon number. The absence of truncating alleles is a real feature of the spectrum, not a gap in ascertainment yet: every published family carries a variant that leaves a protein behind. One allele recurs. p.Glu269Lys was reported independently in a European family and a Turkish family within months of each other in 2019, each report presenting it as novel. Neither addresses whether that is recurrent mutation at a hypermutable site or a shared haplotype, and no haplotype analysis has been published, so the entry records the recurrence without asserting a founder effect. The same is true of the two splice variants: c.981+1G>A and c.981+5G>A are different changes at one donor site in two unrelated Chinese families, which is convergence on a splice junction rather than a shared allele.
Dominant-negative mutant plastin 1 with partial loss of function Reduced plastin 1 dosage from an unstable mutant protein
PLS1 hgnc:9090 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLS1 (hgnc:9090). hgnc:9090 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Actin Cross-Linking by Plastin 1 Dominant-negative mutant plastin 1 with partial loss of function Reduced plastin 1 dosage from an unstable mutant protein
Show evidence (4 references)
PMID:31397523 SUPPORT Human Clinical
"In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin."
The predicted consequence shared by the three founding missense alleles, and - in the word "suggests" - the fact that it is modelling rather than measurement.
PMID:31432506 SUPPORT Human Clinical
"Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL."
Independent recurrence of the same missense allele in an unrelated population, which is stronger gene-disease evidence than three private variants would be.
PMID:36537221 SUPPORT Human Clinical
"We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping."
The first splice allele, and the minigene result establishing that it removes an internal segment rather than truncating the protein.
+ 1 more reference
Impaired Actin Cross-Linking by Plastin 1
Plastin 1 has two tandem actin-binding domains built from paired calponin-homology folds. The second has the higher affinity for actin and the first holds it under autoinhibitory restraint, releasing it only once the first domain has engaged a bundle. Removing the segment encoded at the c.981 donor exon breaks the intramolecular contact between the two domains, and the mutant protein then binds actin bundles in an abnormal pattern and disturbs cytoskeletal organisation rather than simply binding less. The four missense alleles are predicted, by modelling, to destabilise the first domain and weaken F-actin binding; none has been assayed biochemically.
Dominant-negative mutant plastin 1 with partial loss of function
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
actin crosslink formation GO:0051764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin crosslink formation (GO:0051764). GO:0051764 is a biological process from the Gene Ontology. ⚠ ABNORMAL
actin filament binding GO:0051015 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Altered Stereocilia Actin Core Packing and Width
Impaired Mechanoelectrical Transduction Dominant-negative mutant plastin 1 with partial loss of function
Show evidence (3 references)
PMID:41922548 SUPPORT In Vitro
"Immunoprecipitation demonstrated that the ΔExon8 mutation disrupts the intramolecular interaction between the ABD1 and ABD2 domains, while immunofluorescence colocalization revealed that the mutation alters the binding pattern of PLS1 to actin bundles and disturbs cytoskeletal organization."
The measured molecular lesion: not absent binding but altered binding, with the autoinhibitory contact broken.
PMID:41922548 SUPPORT In Vitro
"ABD2 has a higher affinity for actin than ABD1, but ABD1 imposes an autoinhibitory constraint on ABD2. When ABD1 first engages actin bundles, autoinhibition is relieved, allowing ABD2 to initiate effective cross-linking"
The normal regulatory arrangement, which is what makes disrupting the ABD1-ABD2 contact a gain of inappropriate activity as easily as a loss of activity.
PMID:29874122 SUPPORT INDIRECT Model Organism
"Altering the actin cross-linker composition, even as the actin filaments exhibit little to no turnover, provides a mechanism for ongoing remodeling and repair important for stereocilia homeostasis."
Why a cross-linker defect is a lifelong maintenance problem rather than a developmental one: the filaments barely turn over but the cross-linkers on them are continuously exchanged. Indirect - it is a general property of the stereocilium measured with fascin-2, not a PLS1 experiment.
Altered Stereocilia Actin Core Packing and Width
The structural consequence. Plastin 1 is the most abundant cross-linker in vestibular stereocilia by targeted mass spectrometry, and what it does to the actin core is counterintuitive: it makes the packing less ordered, not more. Wild-type stereocilia have randomly arranged, liquid-packed actin filaments; stereocilia lacking plastin 1 have orderly hexagonal packing and are shorter and thinner. Liquid packing is what permits a stereocilium to reach full diameter, so the cross-linker widens the rod by disordering it. In the mouse this is a maintenance failure. Bundles develop normally and the defect appears in young adults, with inner hair cells affected first and outer hair cells degenerating later.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
auditory receptor cell stereocilium organization GO:0060088 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal auditory receptor cell stereocilium organization (GO:0060088). GO:0060088 is a biological process from the Gene Ontology. ⚠ ABNORMAL stereocilium maintenance GO:0120045 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased stereocilium maintenance (GO:0120045). GO:0120045 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Pls1 knockout mouse Mouse recapitulates This is where the structural claim comes from. Actin filament packing inside a stereocilium cannot be measured in a patient, so the mouse is not corroborating a human observation - it is the experiment in which plastin 1's contribution to bundle width was defined, and the direction of the effect (loosening the lattice to allow widening) was not the expected one.
Downstream
Progressive Sensorineural Hearing Impairment
High-Frequency Weighted Hearing Loss Drawn as unknown-intermediate on purpose. A bundle-maintenance defect producing a high-frequency-weighted audiogram is the pattern seen across cochlear hair cell diseases and it is what these patients have, but nothing published shows a base-to-apex gradient of stereocilia change in a PLS1 model, and the mouse null loses hearing across all frequencies rather than at the high end first. The steps between this node and the audiometric configuration are therefore not established for this gene.
Show evidence (4 references)
PMID:27811163 SUPPORT Model Organism
"Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing."
The packing change itself, which is the specific structural role this node names and which distinguishes plastin 1 from the other two cross-linkers.
PMID:27811163 SUPPORT Model Organism
"Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall"
The quantitative case for plastin 1 mattering structurally: it is not a minor component of the bundle.
PMID:27811163 SUPPORT Model Organism
"Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter."
The causal statement linking the packing change to stereocilium diameter.
+ 1 more reference
Impaired Mechanoelectrical Transduction
Transduction is affected, but the mouse null and the human-type mutant are not affected in the same direction and the difference is the most informative measurement in the disease. In Pls1 knockout mice the size of the mechanoelectrical transducer current is unchanged and bundle stiffness is unaffected; only the adaptation properties differ. In zebrafish, FM1-43 uptake through the transduction channel is modestly increased in plastin-1 knockouts - consistent with channels sitting abnormally open - and significantly reduced in larvae expressing the human exon-skipping mutant, consistent with channels that do not open properly. Whether that reflects bundle mechanics, tip-link tension or channel gating has not been determined, which the authors say explicitly. This node therefore records a transduction abnormality whose sign depends on the allele class, and does not assert a mechanism for it.
Dominant-negative mutant plastin 1 with partial loss of function
sensory hair cell CL:0000855 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory hair cell (CL:0000855). CL:0000855 is a cell type from the Cell Ontology.
detection of mechanical stimulus involved in sensory perception of sound GO:0050910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal detection of mechanical stimulus involved in sensory perception of sound (GO:0050910). GO:0050910 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Pls1 knockout mouse Mouse partially recapitulates The null does affect transduction, but narrowly and in the wrong direction to model the human allele. Only adaptation changes; current size and bundle stiffness do not. In zebrafish the equivalent comparison shows the null and the human-type mutant moving transduction-channel dye uptake in opposite directions.
pls1 knockout and human mutant-expressing zebrafish Zebrafish recapitulates The experiment that establishes the transduction defect as a property of the mutant protein rather than of plastin 1 deficiency. Its design is what gives it force: the wild-type rescue arm rules out the injection and the knockout background as explanations.
Downstream
Progressive Sensorineural Hearing Impairment Dominant-negative mutant plastin 1 with partial loss of function
Show evidence (3 references)
PMID:41922548 SUPPORT Model Organism
"This pattern suggests that the MET channels in Pls1-KO fish tend to remain abnormally open, whereas the mutant protein impairs the normal opening of the MET channels, resulting in decreased permeability."
The opposite-direction result that separates the null from the mutant, and the authors' interpretation of it.
PMID:41922548 SUPPORT Model Organism
"However, whether these differences reflect altered bundle mechanics, tip-link tension, or channel gating cannot be determined from the present data and will require direct physiological and ultrastructural analyses."
The authors' statement of what remains unknown, which is why this node stops at "transduction is abnormal" rather than naming a mechanism.
PMID:25124451 SUPPORT Model Organism
"The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents."
The mouse null's narrow transduction phenotype - adaptation changed, current size and stiffness not - which is the measurement the zebrafish mutant result is contrasted against.
⬡

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 76 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
Progressive Sensorineural Hearing Impairment Auditory HP:0001730 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment, annotated with Progressive hearing impairment (HP:0001730), qualified as course progressive. HP:0001730 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:41922548 SUPPORT Human Clinical
"Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
The fullest published description of the audiological course in a single DFNA76 family.
PMID:31432506 SUPPORT INDIRECT Human Clinical
"Out of three major classes of actin-bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance."
The maintenance framing the clinical authors themselves apply to the progressive course. Indirect with respect to the phenotype record because it states the biology rather than reporting these patients' audiograms.
High-Frequency Weighted Hearing Loss Auditory 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 (2 references)
PMID:41922548 SUPPORT Human Clinical
"moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age"
The audiometric configuration in the family with the fullest clinical description.
PMID:41822198 SUPPORT Human Clinical
"At age 6, pure-tone audiometry revealed bilateral symmetric severe hearing loss at medium-to-high frequencies (250-8000 Hz), with abnormal air and bone conduction thresholds"
The counter-example: a proband whose loss spans the medium as well as the high range, which is why this record describes a bias rather than a restriction.
Congenital Onset in Some Families Auditory HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital sensorineural hearing impairment (HP:0008527), qualified as congenital onset. HP:0008527 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:41822198 SUPPORT Human Clinical
"The proband (III-1), a 7-year-old girl, was diagnosed with congenital hearing loss, failing newborn hearing screening, which included otoacoustic emissions and automatic auditory brainstem response"
The documented congenital onset, established objectively rather than by history.
PMID:41822198 SUPPORT Human Clinical
"By contrast, both affected individuals in the present family exhibited prelingual deafness, consistent with other reported NSHL cases caused by PLS1 mutations"
The authors' use of prelingual onset as a discriminating feature. Their claim that it is consistent with other PLS1 reports is recorded as their assessment; the Turkish family was postlingually diagnosed, which is why this entry does not adopt it.
🧬

Genetic Associations

1
PLS1
Gene: PLS1 hgnc:9090 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLS1 (hgnc:9090). hgnc:9090 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:41922548 SUPPORT Other
"PLS1 is predominantly expressed in intestinal epithelial microvilli and stereocilia of cochlear and vestibular hair cells"
The expression pattern, including the extra-auditory site. Graded OTHER because the sentence is this paper's introductory summary of prior work rather than a measurement it made.
PMID:41922548 SUPPORT In Vitro
"According to UniProt, the ubiquitination site (K333) is located only six amino acids downstream of the ΔExon8 deletion region"
The structural reason the mutant protein is destabilised, which connects the splice lesion to the reduced dosage arm of the mechanism.
PMID:31397523 SUPPORT Human Clinical
"PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia."
What the gene encodes and how much of it there is in a stereocilium, from the paper that first tied it to human disease.
💊

Medical Actions

3
Hearing Amplification
Action: hearing aid amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid amplification, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Hearing aids, the first-line intervention, and the one DFNA76 management fact that is actually reported: both affected members of one Chinese family require them for daily life. What is specific to this disorder is the follow-up rather than the fitting. Onset ranges from congenital to adult recognition within the same gene, so a normal audiogram in a young carrier settles nothing, and the loss that does appear progresses - so the useful commitment is repeated aided testing rather than a single decision.
Mechanism Target:
Progressive Sensorineural Hearing Impairment — Compensates for the threshold loss by raising the sound pressure reaching a bundle that is narrowing and shortening but still transducing. It does not act on the actin cross-linking defect or slow the stereocilia degeneration driving it, which is why no treatment_effect value is recorded - every value in that enum asserts a change to the mechanism, and amplification makes no such claim.
Show evidence (2 references)
PMID:41822198 SUPPORT Human Clinical
"At present, both mother and daughter require hearing aids for daily life."
The only reported description of management in a DFNA76 family. It records use, not outcome, and no aided threshold or speech score is published for any PLS1 patient.
PMID:37371710 SUPPORT INDIRECT Other
"A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
Cited at the class level deliberately. This is a narrative review of autosomal dominant nonsyndromic hearing loss as a group, not of DFNA76, so it supports the management approach for the class this disease belongs to. Graded INDIRECT for that reason, and OTHER because it is a review rather than a study. No DFNA76-specific treatment study exists.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Implantation as thresholds deteriorate past what amplification can address, which the reported severity range - mild to profound - makes a real prospect in this disease. Curated separately from amplification because the two differ in what can be said about them: implantation is a surgical procedure with a bindable action term, and no DFNA76-specific outcome series exists, so this record notes the intervention without claiming an outcome for the genotype.
Mechanism Target:
BYPASSES Altered Stereocilia Actin Core Packing and Width — The DFNA76 lesion is inside the hair cell's actin core. An implant stimulates the spiral ganglion electrically and does not need a bundle of normal width, so it operates downstream of the node that fails.
Show evidence (1 reference)
PMID:37371710 SUPPORT INDIRECT Other
"A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
Class-level support for implantation as part of the management pathway for dominant nonsyndromic hearing loss. Graded INDIRECT because the review is about the group, not this disease; no PLS1 implantation outcome is reported anywhere.
Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counselling for a dominant condition with a 50 percent transmission risk. The disease-specific content is what the PLS1 result does not predict: onset spans congenital to adult across reported families, so a normal audiogram in a young carrier does not establish non-penetrance and a family cannot be told when to expect the loss. Formal penetrance has not been estimated in any pedigree.
Show evidence (1 reference)
PMID:41822198 SUPPORT Human Clinical
"By contrast, both affected individuals in the present family exhibited prelingual deafness, consistent with other reported NSHL cases caused by PLS1 mutations"
The congenital end of the onset range in one family, which is half of what makes onset uncounsellable. The authors' claim that it is consistent with other PLS1 reports is theirs; the Turkish family was diagnosed postlingually.
🔬

Diagnosis

1
PLS1 on autosomal dominant nonsyndromic hearing loss panels, with RNA analysis for splice alleles
DFNA76 is reached by a hearing loss gene panel or exome sequencing containing PLS1, with segregation testing across the pedigree. Two of the six reported alleles are splice variants at the same donor site, and neither was called pathogenic on sequence alone - one required a minigene assay and the other reverse-transcription PCR to show exon skipping. A PLS1 splice variant of uncertain significance is therefore a candidate for RNA-level testing rather than a reason to stop looking.
Show evidence (2 references)
PMID:36537221 SUPPORT Human Clinical
"A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing."
The assay that established the first splice allele's consequence.
PMID:41822198 SUPPORT Human Clinical
"This functional evidence meets the 'PS3_Moderate' criterion under ACMG guidelines. Therefore, the c.981+5G>A variant was reclassified from a VUS to 'likely pathogenic'."
The concrete consequence of doing the RNA work: a variant of uncertain significance became actionable.
📈

Progression

2
Onset
Age: congenital to adult recognition
Onset is genuinely heterogeneous rather than uncertain. One Chinese family is congenital and failed newborn screening; the other Chinese family's loss begins in childhood; the Turkish family was diagnosed postlingually. A normal newborn screen therefore does not exclude DFNA76 in a family carrying a PLS1 variant, and a failed one does not contradict the diagnosis either.
Show evidence (1 reference)
PMID:41822198 SUPPORT Human Clinical
"The probands mother, aged 36 years, also exhibited congenital hearing loss, with pure-tone audiometry demonstrating levels markedly above the normal threshold"
The congenital end of the onset range, in two generations of one family.
Progression
Age: childhood onwards
Where the loss begins in childhood it worsens with age, weighted towards the high frequencies. No rate of decline in decibels per year has been published for any DFNA76 family, so surveillance intervals cannot be derived from the literature.
Show evidence (1 reference)
PMID:41922548 SUPPORT Human Clinical
"Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
The reported course, in the only family described in this much detail.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
DFNA76 is known from a small number of families - three of European ancestry in the founding report, one Hungarian Roma family, one Turkish family and two Chinese families. No prevalence or incidence estimate has been published, so no rate_per_100000 is recorded and ULTRA_RARE is a qualitative band rather than a converted figure. PLS1 also contributes to the residual diagnostic yield in large nonsyndromic hearing loss cohorts, which is a different quantity and is not curated here as a prevalence.
Show evidence (1 reference)
PMID:31432506 SUPPORT Human Clinical
"A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported."
The state of the literature when the second family was published: one small family. That is the scale the ULTRA_RARE band records.
🐁

Animal Models

2
Pls1 knockout mouse
The principal in vivo model, and a homozygous null standing in for a heterozygous missense or in-frame-deletion disease. Knockouts have moderate progressive hearing loss across all frequencies. Hair cells develop normally; inner hair cell stereocilia narrow and shorten in young adults, outer hair cell stereocilia are less affected initially and degenerate with age. Bundle stiffness and the acquisition of hair cell electrophysiology are normal, and transducer current size is unchanged, with only adaptation altered. A later cryo-electron-tomography study used the same line to show that the actin filaments of plastin-1-deficient stereocilia adopt orderly hexagonal packing where wild-type filaments are liquid-packed.
Species
Mouse
Genotype
Pls1 -/- (plastin 1 null)
Genes
PLS1 hgnc:9090 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PLS1 (hgnc:9090). hgnc:9090 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:25124451
Pathograph links
Altered Stereocilia Actin Core Packing and Width recapitulates fidelity: high This is where the structural claim comes from. Actin filament packing inside a stereocilium cannot be measured in a patient, so the mouse is not corroborating a human observation - it is the experiment in which plastin 1's contribution to bundle width was defined, and the direction of the effect (loosening the lattice to allow widening) was not the expected one.
Limitations: The packing and width measurements were made in vestibular stereocilia of a homozygous null, and the human disease is heterozygous, cochlear and caused by alleles that produce protein. Nothing here shows that a human missense or in-frame-deletion allele changes actin packing at all.
Readouts
Actin filament packing order in stereocilia
Direction: ALTERED
Interpretation: Packing shifts from liquid to hexagonal without plastin 1, which is the structural change that limits how wide a stereocilium can grow.
Show evidence (1 reference)
PMID:27811163 SUPPORT Model Organism
"Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing."
The packing measurement behind this readout.
Stereocilium width and length
Direction: DECREASED
Interpretation: Inner hair cell stereocilia become narrower and shorter in young adults, after developing normally.
Show evidence (1 reference)
PMID:25124451 SUPPORT Model Organism
"Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length."
The morphometric measurement behind this readout, and its timing.
Show evidence (1 reference)
PMID:27811163 SUPPORT Model Organism
"Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia."
The structural phenotype that makes this line informative for the node.
Impaired Mechanoelectrical Transduction partially recapitulates fidelity: low The null does affect transduction, but narrowly and in the wrong direction to model the human allele. Only adaptation changes; current size and bundle stiffness do not. In zebrafish the equivalent comparison shows the null and the human-type mutant moving transduction-channel dye uptake in opposite directions.
Limitations: Fidelity is LOW because the discrepancy is directional, not merely quantitative. The null's transduction phenotype cannot stand in for the mutant's, and the study that established this was done in zebrafish rather than in the mouse line, so no mouse carrying a human PLS1 allele has been tested. Curating this link at higher fidelity would let a reader infer that anything measured in Pls1 knockout mice applies to DFNA76 patients, which is the specific error this entry exists to avoid.
Readouts
Mechanoelectrical transducer current and adaptation
Direction: ALTERED
Interpretation: Adaptation properties change while transducer current amplitude does not, so the null perturbs how the channel responds over time rather than how many channels there are or how well they open.
Show evidence (1 reference)
PMID:25124451 SUPPORT Model Organism
"The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents."
The electrophysiological measurement behind this readout, including the three things that did not change.
Show evidence (1 reference)
PMID:41922548 SUPPORT INDIRECT Model Organism
"FM1-43 uptake was slightly increased in Pls1-knockout larvae but reduced in the ΔExon8-PLS1 group. These contrasting patterns suggest that PLS1 deficiency and ΔExon8-PLS1 expression may perturb MET channel function through different mechanisms."
Why this link is only partial: knocking the gene out and expressing the human mutant do different things to transduction. Indirect with respect to the mouse model because the comparison was made in zebrafish.
Show evidence (2 references)
PMID:25124451 SUPPORT Model Organism
"Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies."
The auditory phenotype that makes the line informative, and the qualifier - moderate, progressive - that the founding human paper cited as its prior.
PMID:25124451 SUPPORT Model Organism
"Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss."
The prediction this mouse made four years before PLS1 was found in patients, which is the strongest thing that can be said for the model's relevance.
pls1 knockout and human mutant-expressing zebrafish
A four-arm comparison - uninjected control, plastin-1 knockout, knockout plus human wild-type protein, knockout plus the human exon-skipping mutant - that is the only published experiment putting the human allele and simple gene loss side by side in an animal. Knockouts have enlarged otic vesicles and altered otolith diameters, both rescued by wild-type protein; the mutant fails to rescue them. Both knockout and mutant larvae show reduced sound-evoked swimming, but only the mutant reduces FM1-43 uptake through the transduction channel, which is increased in the knockout.
Species
Zebrafish
Genotype
pls1 -/- knockout, and larvae expressing human PLS1 wild-type or the exon-skipping mutant
Genes
PLS1 hgnc:9090 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns PLS1 (hgnc:9090). hgnc:9090 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41922548
Pathograph links
Impaired Mechanoelectrical Transduction recapitulates fidelity: moderate The experiment that establishes the transduction defect as a property of the mutant protein rather than of plastin 1 deficiency. Its design is what gives it force: the wild-type rescue arm rules out the injection and the knockout background as explanations.
Limitations: Zebrafish lateral-line neuromast hair cells are not cochlear hair cells, and FM1-43 uptake is an indirect proxy for channel function that the authors decline to interpret mechanistically. The human protein is expressed on a zebrafish null background rather than beside an endogenous wild-type allele, so the configuration is not the heterozygous one patients are in. Espin and fascin partially compensate for absent plastin 1 in zebrafish stereocilia, which the authors offer as the reason the knockout phenotype is modest - so the null arm may understate what losing plastin 1 does.
Readouts
FM1-43 uptake through the transduction channel in lateral-line neuromasts
Direction: DECREASED
Interpretation: Dye entry falls in larvae expressing the human mutant, indicating channels that open less or are less permeable - the opposite of what happens when plastin 1 is simply absent.
Show evidence (1 reference)
PMID:41922548 SUPPORT Model Organism
"Quantification of FM1-43 fluorescence intensity based on the mean fluorescence intensity of the neuromast region showed that ΔExon8-PLS1 larvae exhibited significantly reduced fluorescence compared with wild-type larvae (Fig. 6D,E), indicating impaired MET channel function."
The measurement behind this readout and its direction in the mutant arm.
Sound-evoked swimming response
Direction: DECREASED
Interpretation: Both knockout and mutant larvae respond less to sound, so the behavioural readout - unlike the dye readout - does not separate the two.
Show evidence (1 reference)
PMID:41922548 SUPPORT Model Organism
"Behavioral assays further demonstrated that both Pls1-KO and ΔExon8-PLS1 larvae exhibited reduced sound-evoked locomotor responses, whereas WT-PLS1 partially restored auditory sensitivity."
The behavioural measurement, recorded alongside the dye readout precisely because it does not distinguish the arms that the dye readout does.
Show evidence (1 reference)
PMID:41922548 SUPPORT Model Organism
"In contrast, ΔExon8-PLS1 failed to rescue these abnormalities and produced phenotypes comparable to those of the knockout, suggesting that the mutation disrupted the essential functions of PLS1 in otolith formation and cytoskeletal homeostasis."
The rescue-failure result establishing that the mutant protein is non-functional for plastin 1's normal jobs, which is the loss-of-function half of the mechanism.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Dominant 76
category: Mendelian
creation_date: "2026-09-01T00:00:00Z"
synonyms:
- DFNA76
- deafness, autosomal dominant 76
- PLS1-related autosomal dominant nonsyndromic hearing loss
- plastin 1 related hearing loss
- fimbrin-related nonsyndromic hearing loss
description: >-
  DFNA76 is autosomal dominant nonsyndromic sensorineural hearing loss caused by
  heterozygous variants in PLS1, which encodes plastin 1 (fimbrin) - one of the three
  actin cross-linkers that build the stereocilium's actin core, and by mass the most
  abundant of them in vestibular bundles. The mechanism is bundle architecture, not
  transduction machinery and not synaptic function.

  Plastin 1 is not needed to build a stereocilium. It is needed to keep one. Knockout mice
  develop normal hair bundles and then lose them: inner hair cell stereocilia narrow and
  shorten in young adults, outer hair cells degenerate later, and hearing declines
  moderately and progressively across all frequencies without early hair cell death. What
  plastin 1 contributes is width. It biases the actin filaments away from tight hexagonal
  packing towards a disordered liquid packing, and it is that looser arrangement that lets a
  stereocilium grow to full diameter.

  The gap between that mouse and the human disease is the central problem of this entry, and
  it is not the usual species caveat. The dose question is partly open rather than untouched:
  Pls1 *heterozygous* nulls shift with age against themselves, hinting at a late and mild
  deterioration, but they never reach a significant deficit against wild-type controls and
  they serve as the paper's normal genotype on every structural and transduction measure. So
  whether one working copy suffices is unsettled in mouse, and whether the human alleles
  behave like a missing copy at all is untested. Every reported human allele is a missense
  change in an actin-binding domain or a splice variant producing an in-frame internal
  deletion - not a truncation, not a whole-gene deletion - so a protein is present in every
  patient. When the two were compared directly in zebrafish,
  they behaved oppositely: dye uptake through the mechanotransduction channel was reduced by
  the mutant protein and increased in the knockout, and neither loss of plastin 1 nor
  re-expression of wild-type protein reproduced the mutant's defect. The authors conclude a
  dominant-negative effect with partial loss of function, and are careful to say that they
  did not co-express wild-type and mutant protein, so the dominant-negative step is inferred
  from the divergence rather than demonstrated.

  Clinically the picture is heterogeneous across a handful of families and should not be
  compressed into one sentence. The Chinese family carrying the exon-skipping allele has
  progressive, unilateral or bilateral, moderate-to-severe high-frequency loss beginning in
  childhood; the Turkish family with p.Glu269Lys had symmetric, moderate, postlingually
  diagnosed progressive loss; a second Chinese family with a nearby splice variant presented
  with congenital loss that failed newborn screening in the proband and in her mother. Onset
  therefore spans congenital to adult, and the only defensible summary is that the loss is
  sensorineural, predominantly high-frequency, and usually progressive once it starts.
disease_term:
  preferred_term: hearing loss, autosomal dominant 76
  term:
    id: MONDO:0032917
    label: hearing loss, autosomal dominant 76
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032917
      label: hearing loss, autosomal dominant 76
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
references:
- reference: PMID:31397523
  title: "Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss."
- reference: PMID:30872814
  title: "Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma."
- reference: PMID:31432506
  title: "Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss."
- reference: PMID:36537221
  title: "A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family."
- reference: PMID:41822198
  title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
- reference: PMID:41922548
  title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
- reference: PMID:25124451
  title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
- reference: PMID:27811163
  title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
- reference: PMID:31962158
  title: "A cryo-tomography-based volumetric model of the actin core of mouse vestibular hair cell stereocilia lacking plastin 1."
- reference: PMID:29874122
  title: "The stable actin core of mechanosensory stereocilia features continuous turnover of actin cross-linkers."
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous PLS1 variants segregating with hearing loss across generations in
    independent families of European, Roma, Turkish and Chinese ancestry. No homozygote or
    compound heterozygote has been reported, and no unaffected carrier has been documented,
    though penetrance has not been formally estimated in any pedigree.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31397523
    reference_title: "Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice."
    explanation: >-
      The founding gene-disease conclusion, stating the inheritance mode. Three unrelated
      dominant pedigrees underlie it, which is what took PLS1 past a single-family
      observation.
  - reference: PMID:30872814
    reference_title: "Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI."
    explanation: >-
      The independent contemporaneous report in a different population, published within
      months of the founding paper and reaching the same inheritance conclusion.
mechanistic_hypotheses:
- hypothesis_group_id: dominant_negative_actin_crosslinking_model
  hypothesis_label: Dominant-negative mutant plastin 1 with partial loss of function
  status: EMERGING
  description: >-
    The mutant protein does something, rather than simply failing to do something. Direct
    comparison in zebrafish separates the two: the exon-8-skipping mutant reduces FM1-43 dye
    uptake through the mechanotransduction channel, while knocking plastin 1 out increases
    it, and neither the knockout nor re-expressed wild-type protein reproduces the mutant's
    reduction. Biochemically the mutant retains actin binding but binds abnormally,
    disrupting the intramolecular ABD1-ABD2 interaction that normally restrains the
    high-affinity domain, and it co-precipitates more ACTG1 than wild-type protein does.

    This is EMERGING rather than CANONICAL for a reason the authors state themselves: they
    did not co-express wild-type and mutant plastin 1, which is the experiment a
    dominant-negative claim requires, so the conclusion is inferred from the functional
    divergence between knockout and mutant rather than demonstrated in the heterozygous
    configuration the patients are actually in. It is also based on one allele. The four
    reported missense alleles have not been through the same analysis, and the modelling
    that predicted them to destabilise the first actin-binding domain is in silico.
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Notably, neither PLS1 deficiency nor re-expression of human wild-type PLS1 in knockout zebrafish reproduces this MET defect. Thus, the mutation not only reduces native PLS1 function but also interferes with normal MET channel activity."
    explanation: >-
      The observation the whole hypothesis rests on: an effect present with the mutant and
      absent both from the null and from wild-type rescue, which is what "not simple loss of
      function" means operationally.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: "We did not directly assess the co-expression of wild-type and mutant PLS1, and future studies are needed to confirm the dominant-negative mechanism under physiologically relevant conditions."
    explanation: >-
      Graded NO_EVIDENCE rather than REFUTE: the sentence reports an experiment that was not
      done. It does not cut against the hypothesis, it is the reason the hypothesis is
      EMERGING.
- hypothesis_group_id: haploinsufficiency_model
  hypothesis_label: Reduced plastin 1 dosage from an unstable mutant protein
  status: ALTERNATIVE
  description: >-
    The simpler reading, and one the same study supports in part. The exon-8-skipping
    protein has a markedly shorter half-life than wild type, is more heavily ubiquitinated,
    and is degraded within twelve hours where the wild-type protein is stable, so cells
    carrying it hold less plastin 1 overall. On this model the disease is a dosage problem
    and the mouse null - moderate, progressive, late-onset loss - is the right model after
    all.

    There is a mouse observation that bears on this model and that the dominant-negative
    framing must not be allowed to obscure - but it is weaker than it first looks, and the
    same paper contains its counterweight.

    What is tested and positive: heterozygous nulls shift with age against *themselves*.
    Wild-type animals show no threshold shift between the youngest and oldest cohorts, and
    heterozygotes show a significant one. What is *not* established: a deficit against
    wild-type controls. On click ABR in animals older than six months there was no
    significant difference between heterozygotes and wild type, and the tone-pip elevation
    described at seven to nine months carries no statistic - the figure legend marks
    significance for knockout versus wild type only. The paper also uses heterozygotes as a
    control genotype throughout its stereocilia morphology, hair cell electrophysiology and
    transduction measurements, where they behave normally.

    So the honest reading is that heterozygous nulls plausibly develop a late, mild
    deterioration, and that halving plastin 1 has never been shown to produce a deficit a
    properly powered comparison would detect. That is suggestive for dosage sufficiency and
    it is not settled.

    Recorded as ALTERNATIVE rather than dismissed because the two are not exclusive and the
    authors present them side by side: reduced stability accounts for the loss-of-function
    component, and the divergent transduction phenotype accounts for the rest. What would
    separate them is a truncating PLS1 allele or a whole-gene deletion in a hearing-impaired
    person; none has been reported.
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CHX-chase experiments revealed rapid degradation of ΔExon8-PLS1 within 12 h, whereas WT-PLS1 remained stable, indicating that the mutation substantially reduced protein stability."
    explanation: >-
      The measured instability that gives the dosage model its footing, from a
      cycloheximide-chase experiment in cells.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unlike the dominant-negative effects described above, this aspect of the phenotype is more consistent with a dosage-insufficient, partial loss-of-function mechanism."
    explanation: >-
      The authors' own separation of the two arms, which is why this entry carries both as
      named hypotheses rather than choosing one.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice aged 7–9 months, hearing thresholds\nwere elevated for het animals for all frequencies tested\nbetween 8 and 32 kHz"
    explanation: >-
      The observation that carries the most weight for this model: a mouse with one
      functional Pls1 copy and no mutant protein develops hearing loss with age. Halving the
      dose is sufficient, which is what haploinsufficiency asserts.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "whereas there was no significant\nthreshold shift between the young and oldest wt animals, there\nwas a significant (P , 0.01) threshold shift between the young-\nest and oldest het animals."
    explanation: >-
      The within-genotype comparison, which rules out ageing as the explanation: wild-type
      animals do not shift over the same period and heterozygotes do. Quoted verbatim from a
      PDF-derived cache, so the less-than sign renders as a comma and the ligatures and line
      breaks are the cache's.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "In animals older than 6\nmonths, hearing thresholds were significantly raised in Pls1\nKO compared with wt (P , 0.001) but there were no significant\ndifferences between Pls1 KO and het, or between het and wt."
    explanation: >-
      Graded REFUTE, and it is the counterweight to the two items above. The comparison that
      would show halving the dose is sufficient - heterozygote against wild type - was made
      and was negative. This paper supports one part of the dosage claim and contradicts
      another, so it is split into separate items rather than cited only where it helps.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: "Significant differences between Pls1 KO and wt thresholds are indicated on (B–D)."
    explanation: >-
      Graded NO_EVIDENCE: the figure legend marks significance for knockout against wild type
      only, so the tone-pip elevation reported for heterozygotes at seven to nine months is
      descriptive rather than a tested difference. Recorded because without it that sentence
      reads as a positive result.
pathophysiology:
- name: PLS1 Heterozygous Variant
  description: >-
    A single altered PLS1 allele. The reported spectrum falls into two classes and contains
    no truncation. Four missense changes sit in or adjacent to the actin-binding regions -
    p.Phe128Ser, p.Leu238Arg and the recurrent p.Glu269Lys in European and Turkish families,
    and p.Leu363Phe in the calponin-homology 2 domain in a Hungarian Roma family. Two splice
    variants at the same donor site, c.981+1G>A and c.981+5G>A, produce an in-frame internal
    deletion of the region encoded by that exon; the two reports number the skipped exon
    differently, so this entry names the donor site rather than an exon number.

    The absence of truncating alleles is a real feature of the spectrum, not a gap in
    ascertainment yet: every published family carries a variant that leaves a protein
    behind.

    One allele recurs. p.Glu269Lys was reported independently in a European family and a
    Turkish family within months of each other in 2019, each report presenting it as novel.
    Neither addresses whether that is recurrent mutation at a hypermutable site or a shared
    haplotype, and no haplotype analysis has been published, so the entry records the
    recurrence without asserting a founder effect. The same is true of the two splice
    variants: c.981+1G>A and c.981+5G>A are different changes at one donor site in two
    unrelated Chinese families, which is convergence on a splice junction rather than a
    shared allele.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PLS1
    term:
      id: hgnc:9090
      label: PLS1
  downstream:
  - target: Impaired Actin Cross-Linking by Plastin 1
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_actin_crosslinking_model
    - haploinsufficiency_model
  evidence:
  - reference: PMID:31397523
    reference_title: "Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin."
    explanation: >-
      The predicted consequence shared by the three founding missense alleles, and - in the
      word "suggests" - the fact that it is modelling rather than measurement.
  - reference: PMID:31432506
    reference_title: "Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL."
    explanation: >-
      Independent recurrence of the same missense allele in an unrelated population, which
      is stronger gene-disease evidence than three private variants would be.
  - reference: PMID:36537221
    reference_title: "A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping."
    explanation: >-
      The first splice allele, and the minigene result establishing that it removes an
      internal segment rather than truncating the protein.
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel variant was identified, namely plastin-1 (PLS1) c.981+5G>A. Functional analysis by reverse transcription PCR revealed that this variant induces exon skipping, establishing its pathogenic mechanism."
    explanation: >-
      The second allele at the same donor site, from an independent family. This is the
      report that numbers the skipped exon 9 where the first numbers it 8.
- name: Impaired Actin Cross-Linking by Plastin 1
  description: >-
    Plastin 1 has two tandem actin-binding domains built from paired calponin-homology
    folds. The second has the higher affinity for actin and the first holds it under
    autoinhibitory restraint, releasing it only once the first domain has engaged a bundle.
    Removing the segment encoded at the c.981 donor exon breaks the intramolecular contact
    between the two domains, and the mutant protein then binds actin bundles in an abnormal
    pattern and disturbs cytoskeletal organisation rather than simply binding less. The four
    missense alleles are predicted, by modelling, to destabilise the first domain and weaken
    F-actin binding; none has been assayed biochemically.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: actin crosslink formation
    term:
      id: GO:0051764
      label: actin crosslink formation
    modifier: ABNORMAL
  downstream:
  - target: Altered Stereocilia Actin Core Packing and Width
    causal_link_type: DIRECT
  - target: Impaired Mechanoelectrical Transduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dominant_negative_actin_crosslinking_model
    intermediate_mechanisms:
    - Stiffened and abnormally arranged actin bundles altering the mechanical context of the transduction channel
    - Altered association of plastin 1 with ACTG1 and MYO1C at the bundle
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoprecipitation demonstrated that the ΔExon8 mutation disrupts the intramolecular interaction between the ABD1 and ABD2 domains, while immunofluorescence colocalization revealed that the mutation alters the binding pattern of PLS1 to actin bundles and disturbs cytoskeletal organization."
    explanation: >-
      The measured molecular lesion: not absent binding but altered binding, with the
      autoinhibitory contact broken.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ABD2 has a higher affinity for actin than ABD1, but ABD1 imposes an autoinhibitory constraint on ABD2. When ABD1 first engages actin bundles, autoinhibition is relieved, allowing ABD2 to initiate effective cross-linking"
    explanation: >-
      The normal regulatory arrangement, which is what makes disrupting the ABD1-ABD2
      contact a gain of inappropriate activity as easily as a loss of activity.
  - reference: PMID:29874122
    reference_title: "The stable actin core of mechanosensory stereocilia features continuous turnover of actin cross-linkers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Altering the actin cross-linker composition, even as the actin filaments exhibit little to no turnover, provides a mechanism for ongoing remodeling and repair important for stereocilia homeostasis."
    explanation: >-
      Why a cross-linker defect is a lifelong maintenance problem rather than a
      developmental one: the filaments barely turn over but the cross-linkers on them are
      continuously exchanged. Indirect - it is a general property of the stereocilium
      measured with fascin-2, not a PLS1 experiment.
- name: Altered Stereocilia Actin Core Packing and Width
  description: >-
    The structural consequence. Plastin 1 is the most abundant cross-linker in vestibular
    stereocilia by targeted mass spectrometry, and what it does to the actin core is
    counterintuitive: it makes the packing less ordered, not more. Wild-type stereocilia
    have randomly arranged, liquid-packed actin filaments; stereocilia lacking plastin 1
    have orderly hexagonal packing and are shorter and thinner. Liquid packing is what
    permits a stereocilium to reach full diameter, so the cross-linker widens the rod by
    disordering it.

    In the mouse this is a maintenance failure. Bundles develop normally and the defect
    appears in young adults, with inner hair cells affected first and outer hair cells
    degenerating later.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
    modifier: ABNORMAL
  - preferred_term: stereocilium maintenance
    term:
      id: GO:0120045
      label: stereocilium maintenance
    modifier: DECREASED
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of hair bundle mechanical fidelity as stereocilia narrow, shorten and degenerate
  - target: High-Frequency Weighted Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn as unknown-intermediate on purpose. A bundle-maintenance defect producing a
      high-frequency-weighted audiogram is the pattern seen across cochlear hair cell
      diseases and it is what these patients have, but nothing published shows a base-to-apex
      gradient of stereocilia change in a PLS1 model, and the mouse null loses hearing across
      all frequencies rather than at the high end first. The steps between this node and the
      audiometric configuration are therefore not established for this gene.
  evidence:
  - reference: PMID:27811163
    reference_title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing."
    explanation: >-
      The packing change itself, which is the specific structural role this node names and
      which distinguishes plastin 1 from the other two cross-linkers.
  - reference: PMID:27811163
    reference_title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall"
    explanation: >-
      The quantitative case for plastin 1 mattering structurally: it is not a minor
      component of the bundle.
  - reference: PMID:27811163
    reference_title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter."
    explanation: The causal statement linking the packing change to stereocilium diameter.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length."
    explanation: >-
      Normal development followed by adult narrowing and shortening, which is what makes
      this a maintenance node rather than a morphogenesis one.
- name: Impaired Mechanoelectrical Transduction
  description: >-
    Transduction is affected, but the mouse null and the human-type mutant are not affected
    in the same direction and the difference is the most informative measurement in the
    disease. In Pls1 knockout mice the size of the mechanoelectrical transducer current is
    unchanged and bundle stiffness is unaffected; only the adaptation properties differ. In
    zebrafish, FM1-43 uptake through the transduction channel is modestly increased in
    plastin-1 knockouts - consistent with channels sitting abnormally open - and
    significantly reduced in larvae expressing the human exon-skipping mutant, consistent
    with channels that do not open properly.

    Whether that reflects bundle mechanics, tip-link tension or channel gating has not been
    determined, which the authors say explicitly. This node therefore records a transduction
    abnormality whose sign depends on the allele class, and does not assert a mechanism for
    it.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in sensory perception of sound
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
    modifier: ABNORMAL
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_actin_crosslinking_model
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This pattern suggests that the MET channels in Pls1-KO fish tend to remain abnormally open, whereas the mutant protein impairs the normal opening of the MET channels, resulting in decreased permeability."
    explanation: >-
      The opposite-direction result that separates the null from the mutant, and the
      authors' interpretation of it.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, whether these differences reflect altered bundle mechanics, tip-link tension, or channel gating cannot be determined from the present data and will require direct physiological and ultrastructural analyses."
    explanation: >-
      The authors' statement of what remains unknown, which is why this node stops at
      "transduction is abnormal" rather than naming a mechanism.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents."
    explanation: >-
      The mouse null's narrow transduction phenotype - adaptation changed, current size and
      stiffness not - which is the measurement the zebrafish mutant result is contrasted
      against.
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Bilateral or, in one reported family, unilateral or asymmetric sensorineural hearing
    loss that worsens with age. The best-characterised course is the Chinese exon-skipping
    family: moderate-to-severe, high-frequency-weighted, beginning in childhood and
    progressing. The Turkish family with p.Glu269Lys was symmetric, moderate and
    postlingually diagnosed, with absent otoacoustic emissions and preserved acoustic
    reflexes. Severity across all reported individuals spans mild to profound. No frequency
    band is given for progression: the total published cohort is a handful of families and
    no series reports what proportion progressed.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0001730
      label: Progressive hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
    explanation: >-
      The fullest published description of the audiological course in a single DFNA76
      family.
  - reference: PMID:31432506
    reference_title: "Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Out of three major classes of actin-bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance."
    explanation: >-
      The maintenance framing the clinical authors themselves apply to the progressive
      course. Indirect with respect to the phenotype record because it states the biology
      rather than reporting these patients' audiograms.
- name: High-Frequency Weighted Hearing Loss
  category: Auditory
  description: >-
    Where the audiometric configuration is described, the loss is worse at high frequencies
    in the Chinese exon-skipping family and in the Hungarian Roma family. The second Chinese
    family is the exception: its proband had severe loss across the medium-to-high range
    from 250 to 8000 Hz, so the high-frequency bias is a tendency rather than a defining
    feature. No frequency value is recorded because no series large enough to compute one
    has been published.
  phenotype_term:
    preferred_term: High-frequency hearing impairment
    term:
      id: HP:0005101
      label: High-frequency hearing impairment
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age"
    explanation: The audiometric configuration in the family with the fullest clinical description.
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 6, pure-tone audiometry revealed bilateral symmetric severe hearing loss at medium-to-high frequencies (250-8000 Hz), with abnormal air and bone conduction thresholds"
    explanation: >-
      The counter-example: a proband whose loss spans the medium as well as the high range,
      which is why this record describes a bias rather than a restriction.
- name: Congenital Onset in Some Families
  category: Auditory
  description: >-
    Not every DFNA76 family presents after speech acquisition. In one Chinese family both
    the proband and her mother had congenital hearing loss, the proband failing newborn
    screening on otoacoustic emissions and automatic auditory brainstem response. The
    authors used that prelingual onset to argue against two competing candidate variants in
    the same proband's mother, both in genes causing postlingual progressive loss - which
    makes the onset a load-bearing part of their diagnostic reasoning rather than an
    incidental observation.

    Curated separately from the progressive record because the two cannot be merged into a
    single onset statement without misdescribing one family or the other.

    This record deliberately has no incoming causal edge. Congenital onset is a timing
    qualifier on the same hearing loss the pathograph already ends in, not a separate
    downstream consequence, and drawing an edge into it would assert that a named mechanism
    node causes the loss to be congenital - a claim nothing in the PLS1 literature supports,
    since the same donor-site region produces congenital loss in one family and childhood
    onset in another.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband (III-1), a 7-year-old girl, was diagnosed with congenital hearing loss, failing newborn hearing screening, which included otoacoustic emissions and automatic auditory brainstem response"
    explanation: The documented congenital onset, established objectively rather than by history.
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, both affected individuals in the present family exhibited prelingual deafness, consistent with other reported NSHL cases caused by PLS1 mutations"
    explanation: >-
      The authors' use of prelingual onset as a discriminating feature. Their claim that it
      is consistent with other PLS1 reports is recorded as their assessment; the Turkish
      family was postlingually diagnosed, which is why this entry does not adopt it.
genetic:
- name: PLS1
  notes: >-
    PLS1 encodes plastin 1, also called fimbrin or I-plastin, one of three plastin isoforms
    in humans. The protein has two N-terminal EF-hand calcium-binding motifs and two tandem
    actin-binding domains, each built from a pair of calponin-homology folds. The second
    domain binds actin with higher affinity and is held under autoinhibitory restraint by
    the first, so cross-linking is a two-step process rather than a simple bivalent grip.
    Outside the ear, plastin 1 is predominantly an intestinal epithelial microvillar
    protein.

    Every reported DFNA76 allele leaves a protein behind - four missense changes clustered
    in or beside the actin-binding regions and two splice variants at one donor site
    producing an in-frame internal deletion. No truncating allele and no whole-gene deletion
    has been reported in a hearing-impaired person, which is why the haploinsufficiency
    model in the hypotheses section remains untested rather than excluded.

    A separate line of work bears on how the mutant behaves in a cell. The exon-skipping
    protein has a ubiquitination site six residues downstream of the deleted region, is more
    heavily ubiquitinated than wild type, and is degraded within twelve hours, so the mutant
    allele contributes both an abnormal protein and less total protein.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PLS1
    term:
      id: hgnc:9090
      label: PLS1
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLS1 is predominantly expressed in intestinal epithelial microvilli and stereocilia of cochlear and vestibular hair cells"
    explanation: >-
      The expression pattern, including the extra-auditory site. Graded OTHER because the
      sentence is this paper's introductory summary of prior work rather than a measurement
      it made.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "According to UniProt, the ubiquitination site (K333) is located only six amino acids downstream of the ΔExon8 deletion region"
    explanation: >-
      The structural reason the mutant protein is destabilised, which connects the splice
      lesion to the reduced dosage arm of the mechanism.
  - reference: PMID:31397523
    reference_title: "Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia."
    explanation: >-
      What the gene encodes and how much of it there is in a stereocilium, from the paper
      that first tied it to human disease.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    DFNA76 is known from a small number of families - three of European ancestry in the
    founding report, one Hungarian Roma family, one Turkish family and two Chinese families.
    No prevalence or incidence estimate has been published, so no rate_per_100000 is
    recorded and ULTRA_RARE is a qualitative band rather than a converted figure. PLS1 also
    contributes to the residual diagnostic yield in large nonsyndromic hearing loss cohorts,
    which is a different quantity and is not curated here as a prevalence.
  evidence:
  - reference: PMID:31432506
    reference_title: "Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported."
    explanation: >-
      The state of the literature when the second family was published: one small family.
      That is the scale the ULTRA_RARE band records.
progression:
- phase: Onset
  age_range: congenital to adult recognition
  notes: >-
    Onset is genuinely heterogeneous rather than uncertain. One Chinese family is congenital
    and failed newborn screening; the other Chinese family's loss begins in childhood; the
    Turkish family was diagnosed postlingually. A normal newborn screen therefore does not
    exclude DFNA76 in a family carrying a PLS1 variant, and a failed one does not contradict
    the diagnosis either.
  evidence:
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands mother, aged 36 years, also exhibited congenital hearing loss, with pure-tone audiometry demonstrating levels markedly above the normal threshold"
    explanation: The congenital end of the onset range, in two generations of one family.
- phase: Progression
  age_range: childhood onwards
  notes: >-
    Where the loss begins in childhood it worsens with age, weighted towards the high
    frequencies. No rate of decline in decibels per year has been published for any DFNA76
    family, so surveillance intervals cannot be derived from the literature.
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
    explanation: The reported course, in the only family described in this much detail.
diagnosis:
- name: PLS1 on autosomal dominant nonsyndromic hearing loss panels, with RNA analysis for splice alleles
  description: >-
    DFNA76 is reached by a hearing loss gene panel or exome sequencing containing PLS1, with
    segregation testing across the pedigree. Two of the six reported alleles are splice
    variants at the same donor site, and neither was called pathogenic on sequence alone -
    one required a minigene assay and the other reverse-transcription PCR to show exon
    skipping. A PLS1 splice variant of uncertain significance is therefore a candidate for
    RNA-level testing rather than a reason to stop looking.
  evidence:
  - reference: PMID:36537221
    reference_title: "A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing."
    explanation: The assay that established the first splice allele's consequence.
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This functional evidence meets the 'PS3_Moderate' criterion under ACMG guidelines. Therefore, the c.981+5G>A variant was reclassified from a VUS to 'likely pathogenic'."
    explanation: >-
      The concrete consequence of doing the RNA work: a variant of uncertain significance
      became actionable.
treatments:
- name: Hearing Amplification
  description: >-
    Hearing aids, the first-line intervention, and the one DFNA76 management fact that is
    actually reported: both affected members of one Chinese family require them for daily
    life. What is specific to this disorder is the follow-up rather than the fitting. Onset
    ranges from congenital to adult recognition within the same gene, so a normal audiogram
    in a young carrier settles nothing, and the loss that does appear progresses - so the
    useful commitment is repeated aided testing rather than a single decision.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid amplification
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_mechanisms:
  - target: Progressive Sensorineural Hearing Impairment
    description: >-
      Compensates for the threshold loss by raising the sound pressure reaching a bundle that
      is narrowing and shortening but still transducing. It does not act on the actin
      cross-linking defect or slow the stereocilia degeneration driving it, which is why no
      treatment_effect value is recorded - every value in that enum asserts a change to the
      mechanism, and amplification makes no such claim.
  evidence:
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At present, both mother and daughter require hearing aids for daily life."
    explanation: >-
      The only reported description of management in a DFNA76 family. It records use, not
      outcome, and no aided threshold or speech score is published for any PLS1 patient.
  - reference: PMID:37371710
    reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
    explanation: >-
      Cited at the class level deliberately. This is a narrative review of autosomal dominant
      nonsyndromic hearing loss as a group, not of DFNA76, so it supports the management
      approach for the class this disease belongs to. Graded INDIRECT for that reason, and
      OTHER because it is a review rather than a study. No DFNA76-specific treatment study
      exists.
- name: Cochlear Implantation
  description: >-
    Implantation as thresholds deteriorate past what amplification can address, which the
    reported severity range - mild to profound - makes a real prospect in this disease.
    Curated separately from amplification because the two differ in what can be said about
    them: implantation is a surgical procedure with a bindable action term, and no
    DFNA76-specific outcome series exists, so this record notes the intervention without
    claiming an outcome for the genotype.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Altered Stereocilia Actin Core Packing and Width
    treatment_effect: BYPASSES
    description: >-
      The DFNA76 lesion is inside the hair cell's actin core. An implant stimulates the
      spiral ganglion electrically and does not need a bundle of normal width, so it operates
      downstream of the node that fails.
  evidence:
  - reference: PMID:37371710
    reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
    explanation: >-
      Class-level support for implantation as part of the management pathway for dominant
      nonsyndromic hearing loss. Graded INDIRECT because the review is about the group, not
      this disease; no PLS1 implantation outcome is reported anywhere.
- name: Genetic Counselling
  description: >-
    Counselling for a dominant condition with a 50 percent transmission risk. The
    disease-specific content is what the PLS1 result does not predict: onset spans congenital
    to adult across reported families, so a normal audiogram in a young carrier does not
    establish non-penetrance and a family cannot be told when to expect the loss. Formal
    penetrance has not been estimated in any pedigree.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, both affected individuals in the present family exhibited prelingual deafness, consistent with other reported NSHL cases caused by PLS1 mutations"
    explanation: >-
      The congenital end of the onset range in one family, which is half of what makes onset
      uncounsellable. The authors' claim that it is consistent with other PLS1 reports is
      theirs; the Turkish family was diagnosed postlingually.
  notes: >-
    No target_mechanisms link is recorded on this treatment. Counselling does not act on a
    pathograph node, and no TreatmentEffectEnum value describes it - INHIBITS, ACTIVATES,
    MODULATES, BYPASSES and RESTORES are all claims about changing a mechanism. The two
    device treatments above carry the section's join points into the graph instead.

    No PLS1-directed drug, antisense oligonucleotide, gene replacement or gene editing has
    been reported, and no DFNA76-specific clinical trial was identified. The
    dominant-negative hypothesis, if confirmed, would make simple gene addition the wrong
    modality here - allele-specific silencing rather than augmentation - which is the
    practical reason the mechanism question in the discussions section matters.
animal_models:
- name: Pls1 knockout mouse
  species: Mouse
  genotype: Pls1 -/- (plastin 1 null)
  publication: PMID:25124451
  description: >-
    The principal in vivo model, and a homozygous null standing in for a heterozygous
    missense or in-frame-deletion disease. Knockouts have moderate progressive hearing loss
    across all frequencies. Hair cells develop normally; inner hair cell stereocilia narrow
    and shorten in young adults, outer hair cell stereocilia are less affected initially and
    degenerate with age. Bundle stiffness and the acquisition of hair cell electrophysiology
    are normal, and transducer current size is unchanged, with only adaptation altered. A
    later cryo-electron-tomography study used the same line to show that the actin filaments
    of plastin-1-deficient stereocilia adopt orderly hexagonal packing where wild-type
    filaments are liquid-packed.
  genes:
  - preferred_term: PLS1
    term:
      id: hgnc:9090
      label: PLS1
  modeled_mechanisms:
  - target: Altered Stereocilia Actin Core Packing and Width
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      This is where the structural claim comes from. Actin filament packing inside a
      stereocilium cannot be measured in a patient, so the mouse is not corroborating a
      human observation - it is the experiment in which plastin 1's contribution to bundle
      width was defined, and the direction of the effect (loosening the lattice to allow
      widening) was not the expected one.
    limitations: >-
      The packing and width measurements were made in vestibular stereocilia of a homozygous
      null, and the human disease is heterozygous, cochlear and caused by alleles that
      produce protein. Nothing here shows that a human missense or in-frame-deletion allele
      changes actin packing at all.
    readouts:
    - name: Actin filament packing order in stereocilia
      target: Altered Stereocilia Actin Core Packing and Width
      direction: ALTERED
      interpretation: >-
        Packing shifts from liquid to hexagonal without plastin 1, which is the structural
        change that limits how wide a stereocilium can grow.
      evidence:
      - reference: PMID:27811163
        reference_title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing."
        explanation: The packing measurement behind this readout.
    - name: Stereocilium width and length
      target: Altered Stereocilia Actin Core Packing and Width
      direction: DECREASED
      interpretation: >-
        Inner hair cell stereocilia become narrower and shorter in young adults, after
        developing normally.
      evidence:
      - reference: PMID:25124451
        reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length."
        explanation: The morphometric measurement behind this readout, and its timing.
    evidence:
    - reference: PMID:27811163
      reference_title: "Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia."
      explanation: The structural phenotype that makes this line informative for the node.
  - target: Impaired Mechanoelectrical Transduction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The null does affect transduction, but narrowly and in the wrong direction to model
      the human allele. Only adaptation changes; current size and bundle stiffness do not.
      In zebrafish the equivalent comparison shows the null and the human-type mutant moving
      transduction-channel dye uptake in opposite directions.
    limitations: >-
      Fidelity is LOW because the discrepancy is directional, not merely quantitative. The
      null's transduction phenotype cannot stand in for the mutant's, and the study that
      established this was done in zebrafish rather than in the mouse line, so no mouse
      carrying a human PLS1 allele has been tested. Curating this link at higher fidelity
      would let a reader infer that anything measured in Pls1 knockout mice applies to
      DFNA76 patients, which is the specific error this entry exists to avoid.
    readouts:
    - name: Mechanoelectrical transducer current and adaptation
      target: Impaired Mechanoelectrical Transduction
      direction: ALTERED
      interpretation: >-
        Adaptation properties change while transducer current amplitude does not, so the
        null perturbs how the channel responds over time rather than how many channels
        there are or how well they open.
      evidence:
      - reference: PMID:25124451
        reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents."
        explanation: >-
          The electrophysiological measurement behind this readout, including the three
          things that did not change.
    evidence:
    - reference: PMID:41922548
      reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "FM1-43 uptake was slightly increased in Pls1-knockout larvae but reduced in the ΔExon8-PLS1 group. These contrasting patterns suggest that PLS1 deficiency and ΔExon8-PLS1 expression may perturb MET channel function through different mechanisms."
      explanation: >-
        Why this link is only partial: knocking the gene out and expressing the human mutant
        do different things to transduction. Indirect with respect to the mouse model
        because the comparison was made in zebrafish.
  evidence:
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies."
    explanation: >-
      The auditory phenotype that makes the line informative, and the qualifier - moderate,
      progressive - that the founding human paper cited as its prior.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss."
    explanation: >-
      The prediction this mouse made four years before PLS1 was found in patients, which is
      the strongest thing that can be said for the model's relevance.
- name: pls1 knockout and human mutant-expressing zebrafish
  species: Zebrafish
  genotype: pls1 -/- knockout, and larvae expressing human PLS1 wild-type or the exon-skipping mutant
  publication: PMID:41922548
  description: >-
    A four-arm comparison - uninjected control, plastin-1 knockout, knockout plus human
    wild-type protein, knockout plus the human exon-skipping mutant - that is the only
    published experiment putting the human allele and simple gene loss side by side in an
    animal. Knockouts have enlarged otic vesicles and altered otolith diameters, both
    rescued by wild-type protein; the mutant fails to rescue them. Both knockout and
    mutant larvae show reduced sound-evoked swimming, but only the mutant reduces FM1-43
    uptake through the transduction channel, which is increased in the knockout.
  genes:
  - preferred_term: PLS1
    term:
      id: hgnc:9090
      label: PLS1
  modeled_mechanisms:
  - target: Impaired Mechanoelectrical Transduction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The experiment that establishes the transduction defect as a property of the mutant
      protein rather than of plastin 1 deficiency. Its design is what gives it force: the
      wild-type rescue arm rules out the injection and the knockout background as
      explanations.
    limitations: >-
      Zebrafish lateral-line neuromast hair cells are not cochlear hair cells, and FM1-43
      uptake is an indirect proxy for channel function that the authors decline to interpret
      mechanistically. The human protein is expressed on a zebrafish null background rather
      than beside an endogenous wild-type allele, so the configuration is not the
      heterozygous one patients are in. Espin and fascin partially compensate for absent
      plastin 1 in zebrafish stereocilia, which the authors offer as the reason the knockout
      phenotype is modest - so the null arm may understate what losing plastin 1 does.
    readouts:
    - name: FM1-43 uptake through the transduction channel in lateral-line neuromasts
      target: Impaired Mechanoelectrical Transduction
      direction: DECREASED
      interpretation: >-
        Dye entry falls in larvae expressing the human mutant, indicating channels that open
        less or are less permeable - the opposite of what happens when plastin 1 is simply
        absent.
      evidence:
      - reference: PMID:41922548
        reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Quantification of FM1-43 fluorescence intensity based on the mean fluorescence intensity of the neuromast region showed that ΔExon8-PLS1 larvae exhibited significantly reduced fluorescence compared with wild-type larvae (Fig. 6D,E), indicating impaired MET channel function."
        explanation: The measurement behind this readout and its direction in the mutant arm.
    - name: Sound-evoked swimming response
      target: Impaired Mechanoelectrical Transduction
      direction: DECREASED
      interpretation: >-
        Both knockout and mutant larvae respond less to sound, so the behavioural readout -
        unlike the dye readout - does not separate the two.
      evidence:
      - reference: PMID:41922548
        reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Behavioral assays further demonstrated that both Pls1-KO and ΔExon8-PLS1 larvae exhibited reduced sound-evoked locomotor responses, whereas WT-PLS1 partially restored auditory sensitivity."
        explanation: >-
          The behavioural measurement, recorded alongside the dye readout precisely because
          it does not distinguish the arms that the dye readout does.
    evidence:
    - reference: PMID:41922548
      reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, ΔExon8-PLS1 failed to rescue these abnormalities and produced phenotypes comparable to those of the knockout, suggesting that the mutation disrupted the essential functions of PLS1 in otolith formation and cytoskeletal homeostasis."
      explanation: >-
        The rescue-failure result establishing that the mutant protein is non-functional for
        plastin 1's normal jobs, which is the loss-of-function half of the mechanism.
discussions:
- discussion_id: pls1_null_mouse_versus_dominant_human_allele
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The main in vivo model of DFNA76 is a homozygous Pls1-null mouse, and the disease is
    dominant in people carrying one missense or in-frame-deletion allele. Zebrafish data say
    the null and the human-type mutant perturb mechanotransduction in opposite directions.
    How much of the mouse phenotype should be read as DFNA76?
  attaches_to:
  - animal_models#Pls1 knockout mouse
  - pathophysiology#Impaired Mechanoelectrical Transduction
  - mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
  rationale: >-
    The Pls1-null mouse has earned its place. It predicted, before any patient was found,
    that human PLS1 mutations would cause relatively mild progressive hearing loss; it is
    where the maintenance role of plastin 1 was established; and it is the material in which
    the actin-packing result was obtained. Every structural claim in this entry's
    pathophysiology depends on it.

    But it is a null, and DFNA76 is not a null disease. Six alleles have been reported and
    not one is truncating: four missense changes in or beside the actin-binding domains, and
    two splice variants at a single donor site that remove an internal segment in frame. A
    protein is made in every reported patient. When the two situations were compared
    directly - the only time they have been - they came apart on the measurement that
    matters most for a mechanosensory cell: dye uptake through the transduction channel fell
    with the human mutant and rose in the knockout, and wild-type protein re-expressed in
    the knockout did not reproduce the mutant's defect.

    So the mouse is a good model of losing plastin 1 and an unknown model of having a
    defective one. That distinction is not academic. If the dominant-negative reading is
    right, gene addition - the modality being developed for recessive deafness genes - would
    add wild-type protein alongside a mutant that is actively interfering, and the
    therapeutic strategy would have to be allele-specific silencing instead. If the dosage
    reading is right, augmentation is exactly right. Nothing published distinguishes them,
    and the experiment that would is not hard: no mouse carrying a human PLS1 missense or
    exon-skipping allele has been made.

    A second, quieter mismatch sits underneath. The zebrafish knockout phenotype is modest,
    and the authors attribute that to espin and fascin partially compensating for absent
    plastin 1 - so the null arm of the comparison may understate the consequence of losing
    the protein, which would narrow rather than widen the gap between the two. That
    possibility has not been tested either.
  evidence:
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Notably, neither PLS1 deficiency nor re-expression of human wild-type PLS1 in knockout zebrafish reproduces this MET defect. Thus, the mutation not only reduces native PLS1 function but also interferes with normal MET channel activity."
    explanation: The direct statement of the mismatch, with the wild-type rescue arm as the control.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Because Espin and Fascin are also expressed in zebrafish stereocilia and can partially compensate for the absence of PLS1"
    explanation: >-
      The reason the knockout arm may understate plastin 1 loss, which is the second-order
      uncertainty inside the comparison.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Therefore, it is essential to define the pathogenic mechanism of each mutation, particularly distinguishing between loss-of-function and dominant-negative mutations."
    explanation: >-
      The authors' framing of why the distinction is a therapeutic question rather than a
      taxonomic one, stated in the context of AAV gene therapy.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "These results show that in contrast to other actin-bundling proteins such as espin, harmonin or Eps8, plastin 1 is dispensable for the initial formation of stereocilia."
    explanation: >-
      What the null model does establish well, recorded so the mismatch is not read as a
      dismissal of the mouse. Indirect with respect to DFNA76 because it describes a
      homozygous null rather than a heterozygous patient allele.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice aged 7–9 months, hearing thresholds\nwere elevated for het animals for all frequencies tested\nbetween 8 and 32 kHz"
    explanation: >-
      The observation that stops this discussion from claiming the mouse cannot model a
      dominant disease at all. Note what it is not: a tested difference against wild type.
      The figure legend marks significance for knockout versus wild type only.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "In animals older than 6\nmonths, hearing thresholds were significantly raised in Pls1\nKO compared with wt (P , 0.001) but there were no significant\ndifferences between Pls1 KO and het, or between het and wt."
    explanation: >-
      Graded REFUTE against the reading that heterozygous nulls are established as affected.
      The comparison was made on click ABR beyond six months and was negative, which is what
      keeps "heterozygous nulls unaffected, knock-in heterozygotes deaf" alive as a possible
      dominant-negative signature.
  - reference: PMID:25124451
    reference_title: "Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Altogether, these results show that the absence of plastin 1\ncauses a moderate form of hearing loss in young adult mice\n(10–20 dB), progressing to a severe loss (40–50 dB) with age."
    explanation: >-
      The magnitude and tempo of the homozygous null phenotype, which is what the human
      course has to be compared against: 10 to 20 dB in young adults reaching 40 to 50 dB
      with age, against patients who fail newborn screening or reach severe loss in
      childhood.
  proposed_experiments:
  - experiment_id: exp_dfna76_knockin_mouse_allele_series
    name: Knock-in mouse allele series for a DFNA76 missense and the exon-skipping allele
    description: >-
      Generate mice carrying the recurrent p.Glu269Lys missense allele and the exon-skipping
      allele in the endogenous Pls1 locus, and phenotype heterozygotes against wild-type,
      Pls1 heterozygous nulls and Pls1 homozygous nulls with auditory brainstem response and
      distortion product otoacoustic emissions across ages, scanning electron microscopy of
      bundle morphology, stereocilium width morphometry, and single-cell transducer current
      and adaptation recordings. The heterozygous-null arm is the critical comparison and it
      is the arm that is currently underpowered: existing data show heterozygotes shifting
      against themselves with age but never reaching a significant deficit against wild type,
      so this experiment has to settle both questions at once - whether heterozygous nulls
      are affected at all on an adequately powered comparison, and, if they are, whether
      knock-in heterozygotes are affected earlier, more severely, or with a transduction
      phenotype of the opposite sign.
    would_support:
    - mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
    supporting_outcome:
    - >-
      Knock-in heterozygotes lose hearing while heterozygous nulls do not, or lose it earlier
      and more severely than nulls of the same age, and their transducer phenotype differs in
      direction from the null's - either result would establish the dominant-negative
      mechanism in the heterozygous configuration patients are in and make allele-specific
      silencing the rational therapeutic target.
    would_refute:
    - mechanistic_hypotheses#dominant_negative_actin_crosslinking_model
    refuting_outcome:
    - >-
      Knock-in heterozygotes and Pls1 heterozygous nulls are indistinguishable in onset,
      severity and transduction phenotype - both late, mild and progressive - which would
      make DFNA76 a haploinsufficiency disease, would retire the dominant-negative
      hypothesis, and would make gene augmentation the appropriate modality.
- discussion_id: pls1_onset_heterogeneity
  kind: KNOWLEDGE_GAP
  prompt: >-
    DFNA76 onset spans congenital to adult across a handful of families. Is that
    allele-driven, and can a family carrying a PLS1 variant be told when to expect the loss?
  attaches_to:
  - phenotypes#Congenital Onset in Some Families
  - phenotypes#Progressive Sensorineural Hearing Impairment
  - progression#Onset
  rationale: >-
    The reported families do not agree about when this disease starts. One Chinese family
    failed newborn screening in two generations. The other Chinese family's loss begins in
    childhood and progresses. The Turkish p.Glu269Lys family was diagnosed postlingually.
    That is a wider onset range than most dominant nonsyndromic hearing loss genes show, and
    it is currently unexplained.

    Two readings are available and neither has been tested. The alleles may differ in
    consequence - the splice variants remove an internal segment while the missense changes
    substitute a single residue, and it would not be surprising if those produced different
    ages of onset. Or onset may vary within an allele, as it demonstrably does for the
    unrelated TPRN null in DFNB79, in which case a modifier or an environmental contribution
    is at work and genotype will never answer the question.

    Distinguishing them needs no new technology, only aggregation: the published families
    are individually too small, but pooling their audiograms by allele would show
    immediately whether the two splice families cluster apart from the missense families.
    Nobody has done it, and the reason is prosaic - the reports are scattered across four
    journals in three countries and no DFNA76 registry exists.

    The counselling stake is concrete. A couple whose child carries a PLS1 variant currently
    cannot be told whether to expect a failed newborn screen, a school-age diagnosis, or
    nothing until adulthood, which changes what surveillance to arrange and when.
  evidence:
  - reference: PMID:41822198
    reference_title: "Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband (III-1), a 7-year-old girl, was diagnosed with congenital hearing loss, failing newborn hearing screening, which included otoacoustic emissions and automatic auditory brainstem response"
    explanation: The congenital pole of the onset range, objectively documented.
  - reference: PMID:41922548
    reference_title: "Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals exhibit progressive, unilateral or bilateral, moderate-to-severe, high-frequency hearing loss that begins in childhood and worsens with age."
    explanation: >-
      A childhood-onset progressive course in a family carrying a splice allele at the same
      donor site as the congenital family's, which is the observation that makes the
      allele-driven explanation hard to sustain on its own.
  - reference: PMID:31432506
    reference_title: "Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL."
    explanation: >-
      The missense family whose postlingual diagnosis is the third point in the onset range.
      Indirect because the abstract establishes the family and the allele without stating
      the age of onset, which is reported in the paper's body.
📚

References & Deep Research

References

10
PMID:31397523
Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss.
No top-level findings curated for this source.
PMID:30872814
Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma.
No top-level findings curated for this source.
PMID:31432506
Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss.
No top-level findings curated for this source.
PMID:36537221
A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family.
No top-level findings curated for this source.
PMID:41822198
Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss.
No top-level findings curated for this source.
PMID:41922548
Pathogenic mechanism of the PLS1 gene variant in hearing loss and functional validation in a zebrafish model.
No top-level findings curated for this source.
PMID:25124451
Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice.
No top-level findings curated for this source.
PMID:27811163
Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid.
No top-level findings curated for this source.
PMID:31962158
A cryo-tomography-based volumetric model of the actin core of mouse vestibular hair cell stereocilia lacking plastin 1.
No top-level findings curated for this source.
PMID:29874122
The stable actin core of mechanosensory stereocilia features continuous turnover of actin cross-linkers.
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 76 (DFNA76, PLS1) · 2026-09-01T18:07:00Z · View source

De novo curation of DFNA76 (MONDO:0032917), heterozygous PLS1/plastin 1. Nothing in kb/ previously mentioned PLS1, so this is a clean start. entry_type decision: DISEASE. One gene, one conserved pathograph (altered plastin 1 -> impaired actin cross-linking -> altered stereocilia actin core packing and width, and a separate branch to impaired mechanoelectrical transduction -> progressive SNHL). Not a SUBTYPE of any curated entry; not a GROUPING. Sources: own PubMed sweep (PLS1/DFNA76/plastin 1 stereocilia) plus an Edison/falcon deep-research report. NEC preflight PASS: PLS1 mentioned 35 times, MONDO OMIM 618787. The central curation decision is that the Pls1-null mouse and the human disease are not the same lesion, and the entry is structured to keep them apart rather than to blend them. Two named mechanistic_hypotheses carry the disagreement: dominant_negative_actin_crosslinking_model (EMERGING) and haploinsufficiency_model (ALTERNATIVE). The 2026 zebrafish study is the only experiment putting the human allele and simple gene loss side by side, and they diverge in direction on FM1-43 uptake through the MET channel; its authors state plainly that they did not co-express wild-type and mutant PLS1, which is curated as supports: NO_EVIDENCE (a limitation reporting an experiment not done, not a refutation). The Pls1-null mouse link to the transduction node is fidelity: LOW for the same reason, with the reasoning written into limitations so a reader cannot infer that mouse transduction data apply to patients. Onset is curated as genuinely heterogeneous rather than uncertain: a separate 'Congenital Onset in Some Families' phenotype records the Chinese family that failed newborn screening in two generations, because merging it with the childhood-onset progressive record would misdescribe one family or the other. A KNOWLEDGE_GAP records that heterogeneity and its counselling cost. Exon numbering: PMID:36537221 calls the skipped exon 8 and PMID:41822198 calls it 9 for variants at the same donor site. The entry names the donor site (c.981) rather than adopting either number. Snippet mechanics: three snippets from PMID:31397523 and PMID:30872814 initially failed because the validator strips bracketed spans that do not match conf/reference_validator_config.yaml literal_bracket_patterns; the fix was to quote bracket-free sentences rather than to widen the config. Deliberately not curated: hearing aids and cochlear implantation as treatments (no PLS1-specific outcome data); the PI3K-AKT transcriptional signal from PLS1 knockdown (cell-line RNA-seq, no patient tissue, and the report itself flags it as hypothesis-generating). Validation: just validate exit 0 with 52/52 snippets verified; check-duplicate-keys, check-entity-refs, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-folded-hyphens all exit 0.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 16 citations 2026-09-01T10:14:54.947714

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hearing Loss Autosomal Dominant 76 (DFNA76, PLS1-related)
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hearing Loss Autosomal Dominant 76 (DFNA76, PLS1-related) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

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

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

10. Diagnostics

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

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

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

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

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

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

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

    Search first: VBO (Vertebrate Breed Ontology)

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

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Hearing Loss, Autosomal Dominant 76 (DFNA76; PLS1-related)

Executive summary

DFNA76 is an ultra-rare Mendelian form of autosomal-dominant, usually nonsyndromic hearing loss caused by heterozygous variants in PLS1, which encodes plastin-1/fimbrin, an actin-filament crosslinker enriched in inner-ear hair-cell stereocilia. Reported disease ranges from congenital, apparently stable hearing impairment in one Hungarian Roma family to childhood- or adult-recognized, progressive, predominantly medium/high-frequency sensorineural hearing loss in other families. The evidence base remains small: principally several families reported in 2019 and one Chinese splice-variant family subsequently investigated with cell and zebrafish models. There are no reliable prevalence estimates, formal penetrance studies, disease-specific clinical criteria, targeted therapies, or PLS1-specific clinical trials.

The following table provides a knowledge-base-oriented synopsis.

Field Evidence-based summary Suggested ontology/identifier
Disease definition DFNA76 is a very rare form of autosomal dominant nonsyndromic hearing loss caused by heterozygous PLS1 variants. Human reports identify PLS1 as a deafness gene in multiple unrelated families; phenotype is isolated hearing loss without consistent syndromic findings (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3). Disease label: Hearing loss, autosomal dominant 76 / DFNA76; MONDO: not confidently verified; MeSH/ICD exact disease-specific ID: not confidently verified
Inheritance Inheritance is autosomal dominant with familial segregation across reported kindreds from Hungarian Roma, Italian, US, French, Turkish, and Chinese families (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3). Formal penetrance estimates have not been established. HP:0000006 Autosomal dominant inheritance
Gene/protein Causal gene: PLS1 (plastin 1, fimbrin), encoding an actin-bundling protein highly expressed in inner-ear stereocilia and also detected in the cuticular plate of hair cells in mouse studies (morgan2019mutationsinpls1 pages 1-2, taylor2015absenceofplastin pages 2-3, xu2022anovelpls1 pages 10-13). Protein architecture includes N-terminal EF-hand calcium-binding motifs and two actin-binding domains, ABD1 and ABD2 (xu2026pathogenicmechanismof pages 1-4, xu2022anovelpls1 pages 10-13). HGNC: PLS1; NCBI Gene/Ensembl/UniProt exact IDs: not confidently verified here; GO suggestions: actin filament binding, actin bundling
Established/reported variants Reported DFNA76-associated variants include p.Leu363Phe in Hungarian Roma family 6012, p.Phe128Ser, p.Leu238Arg, and recurrent p.Glu269Lys in European/Turkish families, plus c.981+1G>A splice variant in a Chinese family (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3, xu2022anovelpls1 pages 10-13). Available summaries indicate these are rare/absent in population databases used in the original studies, but precise allele counts/frequencies are not fully available in current context. Sequence Ontology suggestions: missense_variant; splice_donor_variant
Core phenotype Core phenotype is bilateral or sometimes asymmetric/unilateral nonsyndromic hearing loss, usually sensorineural, often affecting medium-to-high or high frequencies; severity ranges from mild to profound across families. Mixed hearing loss was reported in some Hungarian Roma individuals (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 7-9). HP:0000365 Hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0011003 Abnormality of hearing physiology
Onset/course Onset appears variable across families: congenital/non-progressive in the Hungarian Roma cohort context, versus childhood/post-lingual to adult detection with progressive decline in several other families. One Italian patient was diagnosed at age 8, while an affected mother recognized loss around age 30 (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3). HPO suggestions: HP:0003577 Congenital onset; HP:0003596 Middle age onset; HP:0003676 Progressive hearing impairment
Anatomy/cell/subcellular site Primary site is the inner ear, especially the organ of Corti and cochlear hair-cell stereocilia; vestibular hair-cell expression is also reported in model/mechanistic literature. Subcellular localization includes stereocilia F-actin cores and cuticular plate (taylor2015absenceofplastin pages 2-3, xu2026pathogenicmechanismof pages 1-4). UBERON: inner ear / cochlea / organ of Corti / stereocilium (exact IDs not confidently verified); CL: auditory hair cell (exact ID not confidently verified); GO CC: stereocilium, actin cytoskeleton
Mechanism Best-supported mechanism is disruption of actin bundling/crosslinking in stereocilia, impairing stereocilia architecture and long-term maintenance. Human missense variants are modeled to destabilize ABD1 and weaken F-actin interaction; splice variant c.981+1G>A causes exon 8 skipping or partial deletion in ABD1. PI3K-AKT upregulation is provisional, supported by the 2022 preprint / later 2023 publication stream and cell/zebrafish work, but not yet established as the definitive human disease mechanism (morgan2019mutationsinpls1 pages 1-2, xu2022anovelpls1 pages 10-13, xu2026pathogenicmechanismof pages 1-4, xu2022anovelpls1 pages 13-19). GO suggestions: actin filament bundle assembly, stereocilium organization, sensory perception of sound
Models Pls1 knockout mice develop moderate progressive hearing loss with shortened/thinner inner-hair-cell stereocilia and later degeneration, supporting a maintenance role for plastin 1. Zebrafish expressing/perturbed for the splice-variant context show abnormal otolith/cochlear morphometry and reduced swimming behavior (taylor2015absenceofplastin pages 2-3, taylor2015absenceofplastin pages 1-1, xu2022anovelpls1 pages 10-13). Model systems: mouse knockout; zebrafish transient model
Diagnosis Diagnosis currently relies on audiologic phenotyping plus molecular testing. Reported methods include next-generation sequencing or whole-exome sequencing with segregation testing, Sanger confirmation, and for splice variants, minigene assays to demonstrate aberrant splicing (morgan2019mutationsinpls1 pages 1-2, xu2022anovelpls1 pages 1-4, xu2022anovelpls1 pages 13-19). NCIT suggestions: Genetic Testing; Audiometry; Sanger Sequencing; Whole Exome Sequencing
Treatment No PLS1-specific molecular therapy or genotype-directed clinical trial was identified. Current care is standard hereditary hearing-loss management: longitudinal audiologic follow-up, hearing aids, and cochlear implantation when indicated by severity/function, extrapolating from broader DFNA practice (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5). NCIT suggestions: Hearing Aid Device; Cochlear Implantation; Genetic Counseling
Epidemiology DFNA76 is ultra-rare; evidence is limited to a small number of reported families from several ancestries. No robust prevalence, incidence, sex ratio, or carrier-frequency estimates are available (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3). Orphanet/MONDO prevalence term: not confidently verified
Key evidence gaps Major gaps include lack of validated disease-specific identifiers in readily available context, no firm penetrance estimates, sparse natural-history data, minimal variant-level population frequency detail, no disease-specific QoL/outcome studies, no established modifier genes, no confirmed epigenetic mechanism, and no approved targeted therapy. The PI3K-AKT link remains hypothesis-generating/provisional rather than clinically established (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 13-19). Knowledge-gap annotation; MONDO/HPO/UBERON exact IDs to be added after manual verification

Table: This table summarizes the current evidence base for PLS1-related autosomal dominant nonsyndromic hearing loss (DFNA76), including clinical features, variants, mechanism, models, and gaps. It is designed as a compact artifact for knowledge-base population while clearly flagging uncertain identifiers and provisional mechanistic claims.

1. Disease information

Definition. DFNA76 is isolated hereditary hearing impairment attributable to a heterozygous pathogenic or likely pathogenic PLS1 variant. The principal clinical lesion is cochlear hearing dysfunction; consistent retinal, neurologic, skeletal, renal, or vestibular disease has not been demonstrated. The foundational human studies reported Hungarian Roma, Italian, US, French, and Turkish families, followed by a Chinese family with a splice-site variant. (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3)

Names and identifiers. Appropriate names include hearing loss, autosomal dominant 76; DFNA76; PLS1-related autosomal-dominant nonsyndromic hearing loss; and plastin-1/fimbrin-related hearing loss. The exact disease-specific MONDO, Orphanet, MeSH, ICD-10, and ICD-11 identifiers were not securely recoverable from the retrieved primary literature and should not be inferred. ICD coding in practice would use a general sensorineural-hearing-loss category rather than a DFNA76-specific code. OMIM and ClinVar identifiers should likewise be verified directly against their current records before database ingestion.

Evidence granularity. Clinical descriptions derive from individual pedigrees and patients, subsequently aggregated in locus/gene-level resources. They are not EHR-derived population estimates. Thus, statements about “typical” DFNA76 remain provisional and vulnerable to ascertainment bias.

2. Etiology, risk, protective factors, and gene–environment interaction

The primary cause is a germline heterozygous PLS1 sequence variant that segregates in an autosomal-dominant pattern. Evidence supports missense variants affecting actin-binding regions and a splice-donor variant disrupting exon 8. (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, xu2022anovelpls1 pages 1-4)

A positive family history is the principal clinical risk indicator. Each child of a heterozygous affected individual has a theoretical 50% probability of inheriting the familial variant, although variant-specific penetrance is unknown. No modifier gene, protective allele, sex effect, anticipation, or germline-mosaicism rate has been established. No DFNA76-specific environmental cause or protective diet/lifestyle intervention is known.

Noise exposure, ototoxic medication, infection, and aging can independently damage hearing, but a quantitative PLS1 × environment interaction has not been demonstrated. Avoiding excessive noise and unnecessary ototoxic exposure is therefore prudent general hearing conservation—not proven primary prevention of genetically initiated DFNA76.

3. Phenotypes

The core phenotype is hearing impairment, most often sensorineural, bilateral, symmetric, and more marked at medium-to-high frequencies. Severity across reported individuals ranges from mild to profound. In an Italian family, a 12-year-old had bilateral symmetric, down-sloping medium/high-frequency loss detected at age 8, while her 48-year-old mother had moderate-to-severe high-frequency loss recognized around age 30. Normal bone-conduction assessment, type-A tympanograms, and normal reflexes excluded conductive disease in that family. (morgan2019mutationsinpls1 pages 1-2)

A Turkish family contained five affected people across three generations; four examined individuals had symmetric, moderate, post-lingually diagnosed, progressive sensorineural loss. Otoacoustic emissions were absent while acoustic reflexes were present. No vertigo, dizziness, nystagmus, balance difficulty, or motor-developmental delay was reported. (diaz‐horta2019novelvariantp.e269k pages 1-5)

The Hungarian Roma PLS1 family had mild-to-profound, high-frequency-biased impairment. Two individuals had mixed hearing loss and one had sensorineural loss; concurrent otitis media with effusion in one person may explain at least part of the conductive component. The wider Roma cohort was described as congenital and non-progressive, with diagnoses between ages 2 and 7, illustrating possible interfamily heterogeneity. (schrauwen2019hearingimpairmentlocus pages 2-3, schrauwen2019hearingimpairmentlocus pages 7-9)

No consistent behavioral or laboratory abnormality belongs to DFNA76. Disease-specific tinnitus frequency, speech-recognition trajectories, vestibular-test results, and quality-of-life scores have not been published. Expected functional consequences of significant hearing loss include impaired speech perception—particularly in noise—communication, education, employment, and social participation, but these have not been quantified specifically for PLS1 disease.

Suggested HPO terms: hearing impairment (HP:0000365); sensorineural hearing impairment (HP:0000407); bilateral hearing impairment; high-frequency hearing impairment; progressive hearing impairment; congenital onset where applicable; and mixed hearing impairment only for appropriately phenotyped individuals. Frequencies should be recorded as “unknown,” not universal.

4. Genetic and molecular information

Gene/protein. The causal gene is PLS1; the encoded plastin-1 protein has N-terminal EF-hand calcium-binding motifs and two tandem actin-binding domains, ABD1 and ABD2, each constructed from calponin-homology domains. Reported boundaries in the experimental literature are approximately ABD1 residues 120–379 and ABD2 residues 394–623. (xu2026pathogenicmechanismof pages 1-4, xu2022anovelpls1 pages 10-13)

Reported variants:

  • c.383T>C, p.(Phe128Ser) — missense, reported in a European-ancestry family.
  • c.713G>T, p.(Leu238Arg) — missense, reported in a European-ancestry family.
  • c.805G>A, p.(Glu269Lys) — missense, independently reported in European and Turkish families; modeling predicts destabilized ABD1 and impaired stable PLS1–ACTB interaction.
  • p.(Leu363Phe) — missense in a Hungarian Roma family; affects the CH2 region involved in actin binding.
  • c.981+1G>A — canonical splice-donor variant in a Chinese family; minigene experiments demonstrated exon-8 skipping or a 47-bp deletion, affecting residues approximately 297–327 in ABD1. (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3, xu2022anovelpls1 pages 10-13)

Original investigators filtered rare variants against databases including gnomAD, ESP6500, and the Greater Middle East variome; the Hungarian study used a minor-allele-frequency threshold below 0.02. PLS1 showed reported gnomAD observed/expected values of 0.42 for predicted loss-of-function and 0.76 for missense variation. Exact current allele counts and ClinVar classifications must be rechecked against the current transcript/version before clinical reporting. (schrauwen2019hearingimpairmentlocus pages 2-3, schrauwen2019hearingimpairmentlocus pages 7-9)

All reported disease variants are constitutional/germline. No somatic etiology, recurrent chromosomal rearrangement, copy-number syndrome, epigenetic signature, modifier gene, or disease-specific methylation abnormality is established. The molecular behavior may combine partial loss of function and dominant-negative interference, but this remains less firmly demonstrated for the missense alleles than segregation and phenotype association.

5. Environmental and infectious information

No toxin, pollutant, radiation exposure, occupational agent, smoking pattern, alcohol use, diet, or infectious organism is known to cause PLS1-related DFNA76. These factors can produce independent or additive acquired hearing loss and should be documented clinically. DFNA76 is not infectious or transmissible.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous PLS1 missense or splice-disrupting variant leads to structurally altered or quantitatively/functionally deficient plastin-1 in inner-ear hair cells. (morgan2019mutationsinpls1 pages 1-2, xu2022anovelpls1 pages 10-13)
  2. Altered plastin-1 leads to impaired regulation and crosslinking of stereociliary F-actin; for missense alleles this is supported chiefly by structural modeling, while exon-8 disruption has experimental splicing and model-system support. (morgan2019mutationsinpls1 pages 1-2, xu2026pathogenicmechanismof pages 1-4)
  3. Abnormal F-actin organization results in defective stereocilia width, length, packing, and long-term maintenance; this step is demonstrated in Pls1-null mice. (taylor2015absenceofplastin pages 2-3, taylor2015absenceofplastin pages 1-1)
  4. Progressive stereociliary architectural failure leads to altered hair-bundle/mechanoelectrical-transduction performance; most baseline electrophysiologic properties remain initially preserved in knockout mice, but adaptation is abnormal. (taylor2015absenceofplastin pages 1-1)
  5. Reduced fidelity of cochlear mechanotransduction results in elevated auditory thresholds and predominantly sensorineural hearing loss.
  6. Provisional branch: PLS1 depletion leads to altered expression of PI3K–AKT-associated genes, which may modify hair-cell survival or cytoskeletal homeostasis; causality in human DFNA76 is not established. (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 13-19)

Plastin-1 localizes to stereocilia and the cuticular plate of mouse inner and outer hair cells. It is present in immature stereocilia and retained in mature bundles, supporting a continuing maintenance function. PLS1 is not indispensable for initial bundle formation: knockout hair cells develop, but adult stereocilia become shorter and thinner. The longest-row width is reduced by about 10–20%; minimum inner-hair-cell stereocilium width was approximately 0.15 μm in knockout versus 0.32 μm in wild type. Outer-hair-cell bundles are initially less affected but develop age-related degeneration. Hearing loss is moderate, progressive, and present across tested frequencies without being explained by early hair-cell death. (taylor2015absenceofplastin pages 2-3, taylor2015absenceofplastin pages 1-1)

The Chinese splice-variant experiments reported 478 upregulated and 309 downregulated genes after PLS1 knockdown. Upregulated genes were enriched in PI3K–AKT signaling; qPCR confirmed increased COL6A3, SPP1, ITGB3, and HGF expression. These results came from a cell model/HEI-OC1 context and zebrafish work rather than patient cochlear tissue; accordingly, PI3K–AKT should be annotated as hypothesis-generating. (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 13-19)

No validated disease-specific metabolomic, lipidomic, proteomic, epigenomic, single-cell, spatial-transcriptomic, organoid, or CRISPR-screen signature is available.

Suggested GO terms: actin filament binding; actin filament bundle assembly; actin cytoskeleton organization; stereocilium organization; maintenance of stereocilium; sensory perception of sound; mechanosensory behavior. Suggested cell types: inner hair cell, outer hair cell, auditory hair cell, and vestibular hair cell. Exact GO/CL accession numbers should be ontology-verified before loading.

7. Anatomical structures affected

The primary organ is the inner ear, particularly the cochlea and organ of Corti. The key tissue is mechanosensory epithelium, and the principal cells are inner and outer hair cells. The crucial subcellular structures are the apical stereocilia/F-actin core and cuticular plate. Plastin-1 is also expressed in vestibular hair-cell stereocilia, but a consistent human vestibular syndrome has not been observed. (diaz‐horta2019novelvariantp.e269k pages 1-5, taylor2015absenceofplastin pages 2-3, xu2026pathogenicmechanismof pages 1-4)

Hearing loss is generally bilateral and symmetric, although unilateral/asymmetric presentation has been reported in the later Chinese-family account. No reproducible secondary-organ involvement is known. Suggested anatomy concepts are UBERON inner ear, cochlea, organ of Corti, cochlear duct, and stereocilium; identifiers require formal ontology lookup.

8. Temporal development

Onset is heterogeneous: congenital or early-childhood disease was reported in the Hungarian Roma cohort, childhood detection occurred in the Italian proband, and adult recognition occurred in her mother. Turkish cases were post-lingual with uncertain exact onset. (morgan2019mutationsinpls1 pages 1-2, diaz‐horta2019novelvariantp.e269k pages 1-5, schrauwen2019hearingimpairmentlocus pages 2-3)

The prevalent pattern outside the original Roma family is insidious, chronic, and progressive. The mouse phenotype similarly emerges after essentially normal hair-bundle development and worsens with age, biologically supporting surveillance throughout life. There are no validated clinical stages, progression-rate equations, remission patterns, or disease-specific critical intervention windows. Spontaneous recovery is not expected for established genetic sensorineural loss.

9. Inheritance and population

Inheritance is autosomal dominant. Multigenerational segregation has been observed, including five affected members across three generations in the Turkish family. Formal penetrance and age-dependent penetrance estimates are unavailable; apparent segregation suggests substantial penetrance in ascertained families, but unaffected young carriers cannot be excluded without longitudinal data. (diaz‐horta2019novelvariantp.e269k pages 1-5)

DFNA76 is ultra-rare, known from a small number of families of Hungarian Roma, Italian, US, French, Turkish, Chinese, and other European ancestries. No prevalence per 100,000, annual incidence, carrier frequency, sex ratio, or reliable geographic gradient has been established. The Roma p.(Leu363Phe) allele could reflect a private or population-enriched familial allele, but a founder effect has not been proven. Consanguinity is not etiologically required for this dominant disorder, and anticipation has not been reported.

10. Diagnostics

Diagnosis requires: (1) history, including onset, progression, noise/ototoxic exposure, and three-generation pedigree; (2) otoscopy and tympanometry to exclude conductive disease; (3) age-appropriate pure-tone or behavioral audiometry with air and bone thresholds; (4) speech testing; (5) otoacoustic emissions and, where needed, auditory brainstem responses; and (6) molecular confirmation.

A comprehensive hereditary-hearing-loss NGS panel containing PLS1 is generally preferable to initial single-gene testing because nonsyndromic hearing loss is highly heterogeneous. Exome sequencing is useful when a panel is negative or when the phenotype is atypical; genome sequencing can interrogate structural, deep-intronic, and regulatory variants missed by exome/panel testing. The original reports used NGS/WES, Sanger confirmation, and segregation analysis; the splice-site study added a minigene assay. (morgan2019mutationsinpls1 pages 1-2, xu2022anovelpls1 pages 1-4, xu2022anovelpls1 pages 13-19)

CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion analysis are not first-line tests for a phenotype strongly suggestive of DFNA76 unless additional findings indicate an alternative diagnosis. RNA analysis can clarify splice variants but is not an established routine biomarker. There is no blood chemistry, imaging, biopsy, proteomic, or metabolomic diagnostic marker.

Differential diagnosis includes other dominant nonsyndromic hearing-loss genes—particularly KCNQ4, TECTA, ACTG1, WFS1, POU4F3, MYO6, and EYA4—plus GJB2-related disease, otosclerosis, congenital infection, noise injury, ototoxicity, and syndromic disorders such as Usher syndrome. Lack of retinal or vestibular findings supports a nonsyndromic diagnosis but does not substitute for longitudinal assessment.

Cascade testing should be offered after a familial pathogenic variant is established. Newborn hearing screening may identify congenital cases but can miss mild or later-onset disease.

11. Outcome and prognosis

DFNA76 is not known to shorten life expectancy or cause disease-specific mortality. Morbidity is auditory and depends on onset, severity, progression, speech discrimination, access to amplification, and educational/communication support. Some patients progress from mild/moderate to severe loss; profound loss has occurred in the reported spectrum. (morgan2019mutationsinpls1 pages 1-2, schrauwen2019hearingimpairmentlocus pages 7-9)

No DFNA76-specific survival, disability-weight, EQ-5D, SF-36, PROMIS, treatment-response, or cochlear-implant outcome dataset exists. Residual hearing does not spontaneously regenerate. Serial audiometry is the most practical prognostic measure; genotype-specific prognostic biomarkers are unavailable.

12. Treatment and current implementation

There is no approved PLS1-directed drug, ASO, RNA therapy, gene replacement, gene editing, or cell therapy. No PLS1/DFNA76-specific interventional clinical trial was identified. Current real-world management is phenotype-directed:

  1. periodic audiologic surveillance;
  2. appropriately fitted bilateral hearing aids for aidable loss;
  3. remote-microphone, classroom, workplace, captioning, and communication accommodations;
  4. speech/language and auditory rehabilitation when needed;
  5. cochlear-implant evaluation for severe-to-profound loss with inadequate aided speech understanding;
  6. treatment of coincident conductive disease, such as otitis media; and
  7. genetic counseling and cascade testing.

General 2023 research emphasizes that inner-ear gene replacement, augmentation, and editing are advancing rapidly, but delivery, cell targeting, therapeutic timing, dominant-negative allele suppression, durability, and safety remain major translational barriers. For DFNA76 specifically, a dominant-negative mechanism could require allele-specific silencing or editing rather than simple gene addition; this is expert mechanistic inference, not an existing therapy.

Suggested NCIT concepts include Genetic Testing, Audiometry, Hearing Aid Device, Cochlear Implantation, Speech Therapy, Auditory Rehabilitation, and Genetic Counseling. Pharmacogenomic guidance and combination pharmacotherapy are not applicable.

13. Prevention

The inherited variant cannot presently be prevented by vaccination, medication, diet, or lifestyle. Primary prevention consists of reproductive options after counseling—prenatal diagnosis or PGT-M where legally and ethically appropriate—and general protection from excessive noise and avoidable ototoxicity. Secondary prevention comprises newborn/childhood screening, molecular cascade testing, and regular audiometry to detect progression early. Tertiary prevention comprises prompt amplification, rehabilitation, communication access, and implantation when indicated. There is no immunization or antimicrobial prophylaxis specific to DFNA76.

14. Other species and natural disease

No naturally occurring veterinary PLS1-associated hearing-loss syndrome was identified. The mechanism is evolutionarily conserved because stereociliary actin architecture and plastin-family crosslinking are conserved across vertebrates. DFNA76 has no zoonotic potential and no cross-species transmission.

15. Model organisms

Mouse, genetic knockout. Pls1-null mice reproduce moderate, progressive, pan-frequency hearing loss and adult stereocilia thinning/shortening. Hair-cell differentiation and initial bundle formation are relatively preserved, making this a strong model of downstream stereocilia-maintenance failure. Limitations are that complete knockout may not model heterozygous missense dominant-negative alleles and the human phenotype is more variable in frequency pattern and onset. (taylor2015absenceofplastin pages 2-3, taylor2015absenceofplastin pages 1-1)

A concise primary-study conclusion was: “plastin 1 is dispensable for the initial formation of stereocilia” but is required for preservation of adult stereocilia and optimal hearing. This directly supports maintenance failure rather than a universal congenital morphogenesis defect. (taylor2015absenceofplastin pages 1-1)

Zebrafish, induced/transient variant model. The c.981+1G>A/exon-8-disruption work reported reduced mean otolith distance, anterior and posterior otolith diameters, and cochlear diameter, together with reduced swimming speed and distance; reported morphometric differences were significant at P<0.05. This supports inner-ear and behavioral consequences but does not directly quantify mammalian hearing and may conflate auditory and vestibular behavior. (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 1-4)

Cell model. PLS1 knockdown in an auditory-cell-line context enabled RNA-seq and PI3K–AKT-pathway analysis. This is useful for pathway generation but cannot establish that the same expression changes occur in human cochlear hair cells in vivo. (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 13-19)

Recent developments and evidence appraisal

The most important disease-specific development near the requested 2023–2024 window was publication of the Chinese c.981+1G>A splice-variant work, initially posted in March 2022 and subsequently associated with a 2023 Clinical Genetics publication stream. It expanded PLS1 disease beyond missense alleles and supplied experimental splicing, zebrafish, and transcriptomic evidence. The authors’ abstract-level conclusion was that the variant causes hearing loss by inducing exon-8 skipping/deletion and that PI3K–AKT upregulation “plays an important role”; the latter should remain provisional because it is not corroborated in patient cochlear tissue. (xu2022anovelpls1 pages 10-13, xu2022anovelpls1 pages 1-4)

A central 2019 abstract stated: “We used next-generation sequencing to identify causal variants in PLS1 … in three unrelated families of European ancestry with autosomal dominant NSHL.” It further reported that modeling suggested destabilization of ABD1 and reduced F-actin binding. (morgan2019mutationsinpls1 pages 1-2)

Another 2019 study summarized the likely variant-specific mechanism as hearing loss arising from “loss of a stable PLS1-ACTB interaction.” This is an authoritative structural interpretation, but direct patient-cell biochemical validation remains lacking. (diaz‐horta2019novelvariantp.e269k pages 1-5)

Overall evidence certainty is moderate for the gene–disease relationship, supported by multiple segregating families and a concordant mouse phenotype; moderate for stereociliary actin-maintenance dysfunction; and low-to-preliminary for PI3K–AKT as a necessary human disease pathway. The highest priorities are additional unrelated families, standardized longitudinal audiometry, current ClinVar/gnomAD curation, allele-specific functional assays, heterozygous knock-in models, patient-derived inner-ear organoids, and preclinical testing matched to the dominant molecular mechanism.

Key source links and publication dates

  • Schrauwen et al., European Journal of Human Genetics, published March 2019: https://doi.org/10.1038/s41431-019-0372-y. (schrauwen2019hearingimpairmentlocus pages 2-3)
  • Morgan et al., Human Mutation, published October 2019: https://doi.org/10.1002/humu.23891. (morgan2019mutationsinpls1 pages 1-2)
  • Diaz-Horta et al., Clinical Genetics, published December 2019: https://doi.org/10.1111/cge.13626. (diaz‐horta2019novelvariantp.e269k pages 1-5)
  • Taylor et al., Human Molecular Genetics, 2015: https://doi.org/10.1093/hmg/ddu417. (taylor2015absenceofplastin pages 2-3)
  • Xu et al., preprint posted March 2022: https://doi.org/10.1101/2022.03.17.484618. (xu2022anovelpls1 pages 10-13)

PMIDs were not present in the retrieved evidence records and therefore are not supplied rather than guessed.

References

  1. (morgan2019mutationsinpls1 pages 1-2): Anna Morgan, Daniel C. Koboldt, Elizabeth S. Barrie, Erin R. Crist, Gema García García, Massimo Mezzavilla, Flavio Faletra, Theresa Mihalic Mosher, Richard K. Wilson, Catherine Blanchet, Kandamurugu Manickam, Anne‐Francoise Roux, Paolo Gasparini, Daniele Dell’Orco, and Giorgia Girotto. Mutations in pls1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss. Human Mutation, 40:2286-2295, Oct 2019. URL: https://doi.org/10.1002/humu.23891, doi:10.1002/humu.23891. This article has 37 citations and is from a domain leading peer-reviewed journal.

  2. (diaz‐horta2019novelvariantp.e269k pages 1-5): Oscar Diaz‐Horta, Guney Bademci, Suna Tokgoz‐Yilmaz, Shengru Guo, Faraz Zafeer, Claire J. Sineni, Duygu Duman, Amjad Farooq, and Mustafa Tekin. Novel variant p.e269k confirms causative role of pls1 mutations in autosomal dominant hearing loss. Clinical Genetics, 96:575-578, Dec 2019. URL: https://doi.org/10.1111/cge.13626, doi:10.1111/cge.13626. This article has 16 citations and is from a peer-reviewed journal.

  3. (schrauwen2019hearingimpairmentlocus pages 2-3): Isabelle Schrauwen, Béla I. Melegh, Imen Chakchouk, Anushree Acharya, Abdul Nasir, Alexis Poston, Diana M. Cornejo-Sanchez, Zsolt Szabo, Tamás Karosi, Judit Bene, Béla Melegh, and Suzanne M. Leal. Hearing impairment locus heterogeneity and identification of pls1 as a new autosomal dominant gene in hungarian roma. European Journal of Human Genetics, 27:869-878, Mar 2019. URL: https://doi.org/10.1038/s41431-019-0372-y, doi:10.1038/s41431-019-0372-y. This article has 23 citations and is from a domain leading peer-reviewed journal.

  4. (taylor2015absenceofplastin pages 2-3): Ruth Taylor, Anwen Bullen, Stuart L. Johnson, Eva-Maria Grimm-Günter, Francisco Rivero, Walter Marcotti, Andrew Forge, and Nicolas Daudet. Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice. Human Molecular Genetics, 24:37-49, Aug 2015. URL: https://doi.org/10.1093/hmg/ddu417, doi:10.1093/hmg/ddu417. This article has 79 citations and is from a domain leading peer-reviewed journal.

  5. (xu2022anovelpls1 pages 10-13): Liangpu Xu, Xinrui Wang, Jia Li, Lingji Chen, Haiwei Wang, Shiyi Xu, Yanhong Zhang, Wei Li, Pengcheng Yao, Meihua Tan, Si Zhou, Meihuan Chen, Yali Pan, Xuemei Chen, Xiaolan Chen, Yunliang Liu, Na Lin, Hailong Huang, and Hua Cao. A novel pls1 c.981+1g>a variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the pi3k-akt signaling pathway. Mar 2022. URL: https://doi.org/10.1101/2022.03.17.484618, doi:10.1101/2022.03.17.484618. This article has 0 citations.

  6. (xu2026pathogenicmechanismof pages 1-4): Tingting Xu, Tao Yang, Haiwei Wang, and Liangpu Xu. Pathogenic mechanism of the pls1 gene variant in hearing loss and functional validation in a zebrafish model. Scientific Reports, Apr 2026. URL: https://doi.org/10.1038/s41598-026-47079-4, doi:10.1038/s41598-026-47079-4. This article has 0 citations and is from a peer-reviewed journal.

  7. (schrauwen2019hearingimpairmentlocus pages 7-9): Isabelle Schrauwen, Béla I. Melegh, Imen Chakchouk, Anushree Acharya, Abdul Nasir, Alexis Poston, Diana M. Cornejo-Sanchez, Zsolt Szabo, Tamás Karosi, Judit Bene, Béla Melegh, and Suzanne M. Leal. Hearing impairment locus heterogeneity and identification of pls1 as a new autosomal dominant gene in hungarian roma. European Journal of Human Genetics, 27:869-878, Mar 2019. URL: https://doi.org/10.1038/s41431-019-0372-y, doi:10.1038/s41431-019-0372-y. This article has 23 citations and is from a domain leading peer-reviewed journal.

  8. (xu2022anovelpls1 pages 13-19): Liangpu Xu, Xinrui Wang, Jia Li, Lingji Chen, Haiwei Wang, Shiyi Xu, Yanhong Zhang, Wei Li, Pengcheng Yao, Meihua Tan, Si Zhou, Meihuan Chen, Yali Pan, Xuemei Chen, Xiaolan Chen, Yunliang Liu, Na Lin, Hailong Huang, and Hua Cao. A novel pls1 c.981+1g>a variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the pi3k-akt signaling pathway. Mar 2022. URL: https://doi.org/10.1101/2022.03.17.484618, doi:10.1101/2022.03.17.484618. This article has 0 citations.

  9. (taylor2015absenceofplastin pages 1-1): Ruth Taylor, Anwen Bullen, Stuart L. Johnson, Eva-Maria Grimm-Günter, Francisco Rivero, Walter Marcotti, Andrew Forge, and Nicolas Daudet. Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice. Human Molecular Genetics, 24:37-49, Aug 2015. URL: https://doi.org/10.1093/hmg/ddu417, doi:10.1093/hmg/ddu417. This article has 79 citations and is from a domain leading peer-reviewed journal.

  10. (xu2022anovelpls1 pages 1-4): Liangpu Xu, Xinrui Wang, Jia Li, Lingji Chen, Haiwei Wang, Shiyi Xu, Yanhong Zhang, Wei Li, Pengcheng Yao, Meihua Tan, Si Zhou, Meihuan Chen, Yali Pan, Xuemei Chen, Xiaolan Chen, Yunliang Liu, Na Lin, Hailong Huang, and Hua Cao. A novel pls1 c.981+1g>a variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the pi3k-akt signaling pathway. Mar 2022. URL: https://doi.org/10.1101/2022.03.17.484618, doi:10.1101/2022.03.17.484618. This article has 0 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 3
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 7
Resolved 7
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.