Autosomal dominant nonsyndromic hearing loss 3A (DFNA3A) is sensorineural hearing loss caused by a heterozygous variant in GJB2, the gene encoding the gap-junction protein connexin 26. It is the dominant counterpart of DFNB1, the recessive GJB2-related hearing loss that is the single commonest genetic cause of congenital deafness worldwide - and the contrast between the two is the whole point of curating it separately. DFNB1 is a dosage disease: two loss-of-function alleles leave too little functional connexin 26 and the channel simply is not made. DFNA3A is not. A single mutant allele produces a subunit that is still made and still assembles, and connexin 26 hexamerises into a connexon before that connexon docks with its partner on the neighbouring cell - so one mutant subunit is incorporated into channels that also contain wild-type subunits and degrades them. The founding functional study demonstrated this directly and, importantly, included the control that makes the claim specific: a nonfunctional *recessive* allele co-expressed the same way left wild-type channels untouched. Loss of function and dominant negative are therefore different mechanisms at the same locus, not two descriptions of one. Connexin 26 is expressed at high levels in the supporting cells of the human cochlea, where the gap-junction network is understood to recycle potassium away from hair cells back toward the stria vascularis. Degrading that network - by a net loss of coupling, by altered channel gating, or both - is what produces the hearing loss. Two cautions are curated explicitly rather than left implicit. First, GJB2 alleles reported as dominant have been retracted on re-examination: the M34T (101T>C) allele was described as a DFNA3 allele and then shown not to be sufficient to cause hearing loss, and that refutation is curated as a REFUTE evidence item rather than omitted. Second, dominant GJB2 variants more often cause *syndromic* disease: keratitis-ichthyosis-deafness syndrome, Vohwinkel syndrome, and palmoplantar keratoderma with deafness. This entry is the nonsyndromic form only. A dominant GJB2 pedigree with skin involvement is a different entry.
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name: Autosomal Dominant Nonsyndromic Hearing Loss 3A
creation_date: "2026-08-29T17:50:00Z"
category: Mendelian
description: >-
Autosomal dominant nonsyndromic hearing loss 3A (DFNA3A) is sensorineural hearing
loss caused by a heterozygous variant in GJB2, the gene encoding the gap-junction
protein connexin 26. It is the dominant counterpart of DFNB1, the recessive
GJB2-related hearing loss that is the single commonest genetic cause of congenital
deafness worldwide - and the contrast between the two is the whole point of curating
it separately.
DFNB1 is a dosage disease: two loss-of-function alleles leave too little functional
connexin 26 and the channel simply is not made. DFNA3A is not. A single mutant
allele produces a subunit that is still made and still assembles, and connexin 26
hexamerises into a connexon before that connexon docks with its partner on the
neighbouring cell - so one mutant subunit is incorporated into channels that also
contain wild-type subunits and degrades them. The founding functional study
demonstrated this directly and, importantly, included the control that makes the
claim specific: a nonfunctional *recessive* allele co-expressed the same way left
wild-type channels untouched. Loss of function and dominant negative are therefore
different mechanisms at the same locus, not two descriptions of one.
Connexin 26 is expressed at high levels in the supporting cells of the human
cochlea, where the gap-junction network is understood to recycle potassium away from
hair cells back toward the stria vascularis. Degrading that network - by a net loss
of coupling, by altered channel gating, or both - is what produces the hearing loss.
Two cautions are curated explicitly rather than left implicit. First, GJB2 alleles
reported as dominant have been retracted on re-examination: the M34T (101T>C) allele
was described as a DFNA3 allele and then shown not to be sufficient to cause hearing
loss, and that refutation is curated as a REFUTE evidence item rather than omitted.
Second, dominant GJB2 variants more often cause *syndromic* disease:
keratitis-ichthyosis-deafness syndrome, Vohwinkel syndrome, and palmoplantar
keratoderma with deafness. This entry is the nonsyndromic form only. A dominant GJB2 pedigree
with skin involvement is a different entry.
disease_term:
preferred_term: autosomal dominant nonsyndromic hearing loss 3A
term:
id: MONDO:0011103
label: autosomal dominant nonsyndromic hearing loss 3A
synonyms:
- DFNA3A
- deafness, autosomal dominant 3A
- autosomal dominant nonsyndromic deafness type 3A
- GJB2 autosomal dominant nonsyndromic deafness
- deafness, autosomal dominant nonsyndromic sensorineural 3
- neurosensory nonsyndromic dominant deafness 1
- NSRD1
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
- Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
description: >-
A single heterozygous GJB2 variant is sufficient. This is the feature that
separates the entry from DFNB1 at the same locus and is not a statement about
severity: the founding pedigree segregated profound deafness with one allele.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we study a pedigree containing cases of autosomal dominant deafness and have
identified a mutation in the gene encoding the gap-junction protein connexin 26
(Cx26) that segregates with the profound deafness in the family.
explanation: >-
The founding observation: a GJB2 variant segregating with deafness in a dominant
pedigree.
- reference: PMID:22695344
reference_title: The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in GJB2, encoding connexin 26 (CX26), are causally related to autosomal
recessive form of non-syndromic hearing loss (NSHL) at the DFNB1 locus and
autosomal dominant NSHL at the DFNA3 locus.
explanation: >-
States both inheritance modes at the locus, which is what makes DFNA3A a distinct
entity rather than a description of DFNB1.
pathophysiology:
- name: Heterozygous GJB2 Variant Producing an Assembly-Competent Mutant Subunit
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
The defining lesion. A single GJB2 allele carries a variant whose product is still
synthesised and still able to enter connexon assembly. That is the necessary
condition for dominance at this locus: an allele that produced nothing would leave
the wild-type allele's channels alone and give an unaffected carrier, which is what
the great majority of GJB2 alleles do. The alleles this entry curates - W44C, D46N,
R75W - all sit in or near the first extracellular loop, and the Vohwinkel D66H
allele cited below is in the same domain, whose authors propose it acts on
oligomerisation, docking or gating. Whether dominant alleles cluster there as a
general rule is asserted in the secondary literature but is not curated here: the
deep-research report's lead citation for that claim is the one reference its own
relevance check flagged as off topic, and no better source was found.
genes:
- preferred_term: GJB2
term:
id: hgnc:4284
label: GJB2
genetic_context:
genes:
- preferred_term: GJB2
term:
id: hgnc:4284
label: GJB2
zygosity: HETEROZYGOUS
functional_impact_category: DOMINANT_NEGATIVE
notes: >-
Recorded as DOMINANT_NEGATIVE on the strength of the co-expression experiments
curated on the next node. Not every dominant GJB2 allele need act by the same
route - the 299-300delAT allele truncates the protein, and M34K acts by being
retained in the endoplasmic reticulum and holding wild-type connexin 26 back with
it, which is dominance by a trafficking mechanism rather than by poisoning an
assembled channel. The category is asserted for the mechanism that has been
demonstrated, not for every allele in the entry.
evidence:
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we study a pedigree containing cases of autosomal dominant deafness and have
identified a mutation in the gene encoding the gap-junction protein connexin 26
(Cx26) that segregates with the profound deafness in the family.
explanation: >-
Establishes the gene and the heterozygous state in the founding pedigree.
- reference: PMID:21484990
reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has
been associated with autosomal dominant hearing loss.
explanation: >-
Quantifies how unusual dominance is at this locus, which is the point of the
assembly-competence requirement this node states.
- reference: PMID:12768774
reference_title: "[Mutations in the connexin 26 gene in patients with nonsyndromic hearing impairment]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Heterozygous deletion AT at position 299-300 of Cx26 cDNA, which results in
premature chain termination, was found in a pedigree with autosomal dominant
hereditary nonsyndromic hearing loss.
explanation: >-
An independent dominant pedigree at the same locus, and the reason the
genetic_context note above is hedged: this allele is a truncation, not a missense.
- reference: PMID:33443819
reference_title: Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: >-
Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting
its delivery to the cell surface.
explanation: >-
Documents a second, distinct route to dominance at this locus - endoplasmic
reticulum retention that drags the wild-type protein with it. INDIRECT because
the allele was found in a syndromic patient, so it bears on the mechanism
available to dominant GJB2 alleles rather than on DFNA3A itself.
downstream:
- target: Dominant-Negative Degradation of Connexin 26 Channels
causal_link_type: DIRECT
description: >-
Because connexin 26 hexamerises into a connexon before that connexon docks with
its partner, a mutant subunit that is made and can oligomerise ends up inside
channels built largely of wild-type subunits.
- name: Dominant-Negative Degradation of Connexin 26 Channels
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
description: >-
Co-expression of the dominant W44C mutant with wild-type connexin 26 at an equal
ratio dramatically reduced intercellular conductance, and what conductance remained
gated abnormally. The control is what makes this a mechanism rather than an
observation: a nonfunctional *recessive* allele, W77R, co-expressed the same way,
neither reduced wild-type channel formation nor altered gating. So the recessive
allele is inert toward its wild-type partner and the dominant one is not, at the
same locus and in the same assay.
Work on a second dominant allele, R75W, localises the defect more precisely, and
the result is not what a naive poison-subunit model predicts. R75W subunits do form
hemichannels - with altered voltage dependence and reduced permeability - but those
hemichannels cannot dock into functional gap-junction channels with the cell next
door. The dominance is therefore a property of the docking step, not of hemichannel
assembly. That distinction matters for therapy: it separates this disease from the
syndromic connexin 26 disorders, where the pathology is attributed to hemichannels
that are too active rather than to junctions that fail to form.
molecular_functions:
- preferred_term: gap junction channel activity
term:
id: GO:0005243
label: gap junction channel activity
modifier: DECREASED
biological_processes:
- preferred_term: gap junction assembly
term:
id: GO:0016264
label: gap junction assembly
modifier: DECREASED
cellular_components:
- preferred_term: gap junction
term:
id: GO:0005921
label: gap junction
evidence:
- reference: PMID:12064630
reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Moreover, W44C dramatically inhibited intercellular conductance of HCx26wt when
co-expressed in an equal ratio, and the low levels of residual conductance
displayed altered gating properties.
explanation: >-
The primary experimental result: a dominant allele degrades wild-type channel
function when the two are co-expressed.
- reference: PMID:12064630
reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
A nonfunctional recessive mutation (W77R) did not inhibit the ability of HCx26wt
to form functional channels when co-injected in the same oocyte pairs, nor did it
alter HCx26wt gating.
explanation: >-
The specificity control. Without it the W44C result would be consistent with any
nonfunctional allele being dominant; with it, dominance is a property of the
particular allele rather than of losing function.
- reference: PMID:16009703
reference_title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, we show that Cx26 R75W forms gap-junctional hemichannels that display
altered voltage dependency and reduced permeability, and which cannot form
functional gap-junctional channels between neighboring cells.
explanation: >-
Locates the defect at the docking step: hemichannels form, junctions do not.
- reference: PMID:16009703
reference_title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The R75W phenotype is dominant at the gap-junction channel but not at the
hemichannel level.
explanation: >-
States the dissociation explicitly, which is what separates this mechanism from
the hyperactive-hemichannel mechanism of the syndromic connexin 26 disorders.
- reference: PMID:22547955
reference_title: GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
Nonsyndromic deafness is caused prevalently by a loss-of-function, while
literature evidences suggest for syndromic deafness a mechanism based on
gain-of-function.
explanation: >-
The review's statement of the same dichotomy at the level of the whole locus.
INDIRECT because it is an expert summary of the literature rather than a result,
and because "loss of function" is a coarser description than the docking defect
the primary work localises.
downstream:
- target: Loss of Cochlear Supporting-Cell Coupling
causal_link_type: DIRECT
- name: Loss of Cochlear Supporting-Cell Coupling
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Connexin 26 is expressed at high levels in the human cochlea, where the non-sensory
supporting cells of the organ of Corti are coupled into a gap-junction network.
Degrading the channels degrades that network.
What is transmitted through it is not only current. A knock-in mouse carrying the
deafness-associated connexin 30 T5M mutation - a paralogue of connexin 26 that
co-assembles with it in the same cells - separates the two kinds of coupling
cleanly: electrical coupling measured by dual patch clamp was normal, while
transfer of a fluorescent tracer and intercellular calcium signalling were both
reduced, and the mice were deaf. Biochemical coupling can therefore fail on its own
and produce hearing loss. The classic account of connexin deafness as a potassium
recycling problem is at best incomplete.
PROVISIONAL rather than ESTABLISHED because the dominant-negative demonstrations
are in heterologous cells and the biochemical-coupling result is in a different
gene's mouse; no coupling measurement has been made in a DFNA3A cochlea.
cell_types:
- preferred_term: organ of Corti supporting cell
term:
id: CL:0002490
label: organ of Corti supporting cell
biological_processes:
- preferred_term: gap junction-mediated intercellular transport
term:
id: GO:1990349
label: gap junction-mediated intercellular transport
modifier: DECREASED
- preferred_term: calcium-mediated signaling
term:
id: GO:0019722
label: calcium-mediated signaling
modifier: DECREASED
evidence:
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high
levels of expression.
explanation: >-
Places the protein in the tissue the disease affects, in human material.
- reference: PMID:20858605
reference_title: The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
In the developing cochlea, electrical coupling, probed by dual patch-clamp
recordings, was normal. However, transfer of the fluorescent tracer calcein
between cochlear non-sensory cells was reduced, as was intercellular Ca(2+)
signalling due to spontaneous ATP release from connexin hemichannels.
explanation: >-
Dissociates biochemical from electrical coupling and shows the biochemical arm is
sufficient for hearing loss. INDIRECT: the mutation is in connexin 30, not
connexin 26, so the inference to DFNA3A rests on the two proteins sharing the same
cells and channels.
- reference: PMID:25625422
reference_title: "Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: >-
Gap junction channels (GJCs) allow metabolic and electrical coupling between
adjacent cells and are formed by the oligomerization of connexin (Cx) protein
subunits.
explanation: >-
States what the network being lost actually carries - metabolic as well as
electrical coupling. INDIRECT: general connexin biology from a paper about
syndromic mutants.
downstream:
- target: Failure of Organ of Corti Maturation
causal_link_type: DIRECT
- target: Cortilymph Potassium Homeostasis Disruption
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Failure of Organ of Corti Maturation
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
The step this entry would have missed without the mouse. Transgenic mice expressing
the dominant-negative R75W connexin 26 allele are severely to profoundly deaf, and
the lesion is a *developmental* failure of the supporting-cell scaffold: the tunnel
of Corti, Nuel's space and the spaces around the outer hair cells never form, inner
pillar cells have too few microtubules, and the organ of Corti is short and its
cells are enlarged in cross-section.
Graded PROVISIONAL rather than ESTABLISHED despite three converging papers, because
those three papers share authorship, one transgenic line and one allele, at an
expression ratio the model's own limitations concede is non-physiological, with no
human histopathology anywhere. Convergent within a lab is not independent.
Two negatives make this the primary lesion rather than a consequence. The outer
hair cells themselves develop normally, keep their subsurface cisternae and their
prestin, and show normal electromotility in isolation - yet distortion-product
otoacoustic emissions are absent at every frequency, because the compressed
supporting-cell architecture will not let them work in situ. And the stria
vascularis is structurally normal.
cell_types:
- preferred_term: organ of Corti supporting cell
term:
id: CL:0002490
label: organ of Corti supporting cell
- preferred_term: cochlear outer hair cell
term:
id: CL:0000601
label: cochlear outer hair cell
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We established two lines of transgenic mice that showed severe to profound hearing
loss, deformity of supporting cells, failure in the formation of the tunnel of
Corti and degeneration of sensory hair cells.
explanation: >-
The founding in vivo result for this node, in a mouse carrying a human
dominant-negative allele.
- reference: PMID:18793701
reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histological observations at postnatal days (P) 5-14 were characterized by i)
absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair
cells
explanation: >-
Times the defect to postnatal development and specifies the architectural
failure.
- reference: PMID:18793701
reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
On the other hand, the development of the sensory hair cells, at least from P5 to
P12, was not affected.
explanation: >-
The negative that makes the supporting cell the primary target and the hair cell
a downstream casualty.
- reference: PMID:19712724
reference_title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The present study indicates that normal development of the supporting cells is
indispensable for proper cellular function of the OHC.
explanation: >-
States the dependency this node asserts: intact hair cells cannot function inside
a malformed scaffold.
downstream:
- target: Secondary Sensory Hair Cell Degeneration
causal_link_type: DIRECT
- name: Cortilymph Potassium Homeostasis Disruption
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Where the potassium story actually lives in this disease, and it is not where the
textbook account puts it. The dominant-negative mouse sustains a normal endolymphatic
resting potential and has a structurally normal stria vascularis, so the lesion is
not a failure to generate the endocochlear potential. What the authors propose
instead is disturbed homeostasis of cortilymph, the extracellular space immediately
around the hair cells, from impaired potassium transport by the supporting cells
themselves.
This entry originally modelled the step as endolymphatic potassium recycling, which
is the standard account of GJB2 deafness; the mouse data say that compartment is
intact. The node is kept PROVISIONAL because the cortilymph account is the
authors' inference from a preserved endocochlear potential plus a degenerating
organ of Corti, not a direct measurement of cortilymph potassium.
biological_processes:
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: DECREASED
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results suggest that the GJB2 mutation disturbs homeostasis of cortilymph,
an extracellular space surrounding the sensory hair cells, due to impaired K(+)
transport by supporting cells, resulting in degradation of the organ of Corti,
rather than affecting endolymph homeostasis in mice and probably in humans.
explanation: >-
The authors' own localisation of the potassium defect to cortilymph and away from
endolymph.
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
The high resting potential in cochlear endolymph essential for hair cell
excitation was normally sustained.
explanation: >-
Curated as REFUTE against the claim that this disease works by failure of the
endocochlear potential. The measurement is a normal result, and it is the reason
this node is about cortilymph rather than endolymph.
downstream:
- target: Secondary Sensory Hair Cell Degeneration
causal_link_type: DIRECT
- name: Secondary Sensory Hair Cell Degeneration
conforms_to: "sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death"
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
description: >-
Hair cells are lost, but downstream of the supporting-cell lesion rather than as
the primary target. PROVISIONAL for the same reason as the node above: the ordering
rests on one lab's transgenic line, not on independent replication or human
material. The module's hair-cell node is entered here through scaffold
failure and cortilymph disturbance, which is what this entry substitutes for the
module's generic insult.
cell_types:
- preferred_term: cochlear outer hair cell
term:
id: CL:0000601
label: cochlear outer hair cell
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We established two lines of transgenic mice that showed severe to profound hearing
loss, deformity of supporting cells, failure in the formation of the tunnel of
Corti and degeneration of sensory hair cells.
explanation: >-
Reports the hair cell degeneration alongside the supporting-cell deformity that
precedes it.
- reference: PMID:19712724
reference_title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
No detectable distortion product otoacoustic emissions were observed at any
frequencies in R75W transgenic mice throughout development.
explanation: >-
Shows outer hair cell function is absent in vivo even while the cells themselves
are intact, which is what makes the loss secondary.
downstream:
- target: Progressive Sensorineural Hearing Loss
causal_link_type: DIRECT
- name: Progressive Sensorineural Hearing Loss
conforms_to: "sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss"
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
description: >-
The clinical endpoint: bilateral sensorineural hearing loss without systemic
features. Severity in reported dominant pedigrees ranges from moderate to profound.
biological_processes:
- preferred_term: sensory perception of sound
term:
id: GO:0007605
label: sensory perception of sound
modifier: DECREASED
evidence:
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we study a pedigree containing cases of autosomal dominant deafness and have
identified a mutation in the gene encoding the gap-junction protein connexin 26
(Cx26) that segregates with the profound deafness in the family.
explanation: >-
Documents the clinical endpoint - profound deafness segregating dominantly.
- reference: PMID:21484990
reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, we present two families with autosomal dominant nonsyndromic
hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn).
explanation: >-
An independent pair of dominant nonsyndromic families, confirming the endpoint is
not specific to the founding pedigree.
phenotypes:
- category: Auditory
name: Sensorineural Hearing Impairment
frequency: OBLIGATE
description: >-
Bilateral sensorineural hearing loss, the sole feature of the disease. Reported
severity in dominant GJB2 pedigrees spans moderate to profound.
phenotype_term:
preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral sensorineural hearing impairment
onset:
notes: >-
onset_category is deliberately left unset. The founding pedigree's deafness is
profound and prelingual, and the mouse lesion is a failure of postnatal organ of
Corti development, which together suggest a congenital presentation - but no
age-of-onset series exists for DFNA3A, and dominant GJB2 pedigrees with later,
progressive loss are also reported. Asserting CONGENITAL would put a claim in a
filterable slot that the evidence does not carry, and a consumer filtering on
onset_category would never see this qualification.
evidence:
- reference: PMID:12064630
reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Cx26 has been implicated in dominant (DFNA3) and recessive (DFNB1) forms of
nonsyndromic sensorineural deafness.
explanation: >-
Names the phenotype and its dominant form. The item is graded IN_VITRO because
the paper is a functional study; the sentence is its framing of the clinical
entity rather than a clinical observation of its own, which is why it is not the
only support for this phenotype.
- reference: PMID:21484990
reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, we present two families with autosomal dominant nonsyndromic
hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn).
explanation: >-
Human observation of the defining phenotype in two independent dominant families.
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we study a pedigree containing cases of autosomal dominant deafness and have
identified a mutation in the gene encoding the gap-junction protein connexin 26
(Cx26) that segregates with the profound deafness in the family.
explanation: >-
The founding human pedigree, cited here so the disease-defining phenotype does not
rest on a functional paper's background sentence.
- category: Auditory
name: Profound Hearing Loss in the Founding Pedigree
frequency: OCCASIONAL
description: >-
The pedigree in which dominant GJB2 deafness was first identified had profound
hearing loss. Recorded as OCCASIONAL rather than as the typical severity because a
single founding pedigree cannot establish the distribution, and other dominant GJB2
families are reported as less severe.
phenotype_term:
preferred_term: Profound sensorineural hearing impairment
term:
id: HP:0011476
label: Profound sensorineural hearing impairment
evidence:
- reference: PMID:9139825
reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified a mutation in the gene encoding the gap-junction protein connexin 26
(Cx26) that segregates with the profound deafness in the family
explanation: >-
Records the severity in that specific family, which is all this item claims.
- category: Constitutional
name: Absence of Systemic or Cutaneous Features
frequency: OBLIGATE
description: >-
Nonsyndromic by definition. This is a curation-relevant negative rather than a
finding: dominant GJB2 variants more often produce syndromic disease, namely
keratitis-ichthyosis-deafness syndrome, Vohwinkel syndrome, and palmoplantar
keratoderma with deafness. Skin, eye or nail involvement therefore moves the
patient out of this entry and into one of those.
evidence:
- reference: PMID:10369869
reference_title: A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results provide evidence that a specific mutation in Cx26 can impair
epidermal differentiation, as well as inner ear function.
explanation: >-
Establishes the syndromic alternative that this entry is being distinguished
from. INDIRECT because it supports the boundary of the entry rather than a
feature within it.
genetic:
- name: GJB2
gene_term:
preferred_term: GJB2
term:
id: hgnc:4284
label: GJB2
relationship_type: CAUSATIVE
notes: >-
One gene, two diseases, two mechanisms. The same locus carries DFNB1 (biallelic
loss of function, common) and DFNA3A (a single dominant-acting allele, rare), and
it also carries the dominant syndromic connexin 26 disorders. Which entry a
GJB2-positive patient belongs to is decided by zygosity and by the presence or
absence of extra-auditory features, not by the gene.
Two named alleles are worth knowing. W44C is the allele in which the
dominant-negative mechanism was demonstrated. M34T (101T>C) is the cautionary one:
reported as a DFNA3 allele and subsequently shown not to be sufficient to cause
hearing loss, with the refutation curated below.
evidence:
- reference: PMID:12522692
reference_title: "Connexin26 gene ( GJB2): prevalence of mutations in the Chinese population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The connexin26 gene ( GJB2) has been shown to be responsible for DFNB1 and DFNA3
(Autosomal Recessive Hereditary Nonsyndromic Deafness Locus 1 and Autosomal
Dominant Hereditary Nonsyndromic Deafness Locus 3).
explanation: >-
States the two-locus, one-gene relationship that the entry's boundary rests on.
- reference: PMID:21484990
reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both families were ascertained from the same village in northern Iran consistent
with a founder effect.
explanation: >-
Records that regional founder alleles occur even within this rare dominant subset,
which bears on how a testing strategy should be scoped geographically.
- reference: PMID:9529365
reference_title: Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
These results indicate that 101T-->C is not sufficient to cause hearing loss.
explanation: >-
Refutes the assignment of the M34T allele to DFNA3A. Curated as REFUTE rather
than omitted because the claim it refutes is in the literature and a curator
matching a patient's M34T result to this entry would otherwise repeat the error.
- reference: PMID:9529365
reference_title: Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
This allele was found in a recessive family segregating independently from the
hearing-loss phenotype and in 3 of 192 control chromosomes.
explanation: >-
The observation behind the refutation: the allele fails to segregate and appears
in controls.
- name: GJB2 c.35delG in trans
gene_term:
preferred_term: GJB2
term:
id: hgnc:4284
label: GJB2
relationship_type: MODIFIER
notes: >-
A loss-of-function GJB2 allele inherited in trans with a dominant-acting one is not
a second cause but a severity modifier, and it is worth knowing about because it
breaks the tidy zygosity rule that otherwise separates this entry from DFNB1: the
patient is heterozygous for the dominant allele and simultaneously a compound
heterozygote at the locus. Reported for a syndromic dominant allele rather than a
DFNA3A one, so this entry records the mechanism rather than asserting it happens
here.
evidence:
- reference: PMID:33443819
reference_title: Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
The presence of a loss a function variant on the other allele creates a more
severe clinical phenotype, with some features reminiscent of KID syndrome.
explanation: >-
Documents a trans loss-of-function allele worsening a dominant GJB2 phenotype.
INDIRECT because the reported patient has syndromic disease, not DFNA3A.
diagnosis:
- name: Audiometry
description: >-
Pure-tone audiometry establishes the sensorineural hearing loss and its severity.
It cannot distinguish DFNA3A from DFNB1 or from any other nonsyndromic cause; that
requires the pedigree and the genotype.
diagnosis_term:
preferred_term: audiometric test
term:
id: NCIT:C38036
label: Audiometric Test
evidence:
- reference: PMID:20301449
reference_title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
In countries where available, newborn hearing screening (NBHS) typically
identifies severe-to-profound hearing loss.
explanation: >-
Describes how GJB2-related hearing loss reaches medical attention. INDIRECT: the
GeneReviews chapter covers the recessive form, and is cited here for the
audiological pathway the two forms share.
- name: Molecular Genetic Testing of GJB2
description: >-
GJB2 sequencing is already the first-line genetic test for nonsyndromic hearing
loss. What assigns DFNA3A is not finding a GJB2 variant but finding a single one
that segregates dominantly - so the interpretation, not the assay, is what
distinguishes this entry, and a heterozygous GJB2 variant in a sporadic case is far
more likely to be carrier status for DFNB1.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:22695344
reference_title: The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 2322 deaf probands presenting the ethnically diverse Iranian
population were screened for variants in GJB2.
explanation: >-
Shows GJB2 screening as the routine first-line test in deaf probands, which is the
context in which a dominant allele is found.
treatments:
- name: Hearing Aid Amplification
therapeutic_modality: DEVICE
description: >-
Amplification for mild-to-moderate loss, the first-line intervention where residual
hearing can be usefully amplified. Outcomes are good because the lesion is cochlear
and the auditory nerve is intact.
notes: >-
Curation note, not clinical content. Hearing aid amplification and cochlear
implantation are curated as separate treatments because they are different devices
for different degrees of loss, and DFNA3A spans both. Both are nonetheless bound to
the generic Therapeutic Procedure action term: NCIT:C183182 Hearing Aid and
NCIT:C157820 Cochlear Implant name the *devices* and are not reachable from
NCIT:C25218 Clinical Intervention or Procedure, so they fail the TreatmentActionTerm
dynamic enum. Presence in cache/ncit/terms.csv does not establish enum membership.
The device distinction is carried by therapeutic_modality and by the treatment names
instead.
treatment_term:
preferred_term: therapeutic procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:20301449
reference_title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
Children with mild-to-moderate hearing loss can be treated with hearing aids
customized to the child's age and severity of hearing loss.
explanation: >-
Gives the indication for amplification in GJB2-related hearing loss. INDIRECT: the
chapter covers the recessive form, and the recommendation is carried over on the
basis that the cochlear lesion is the same.
- name: Cochlear Implantation
therapeutic_modality: DEVICE
description: >-
Implantation for severe-to-profound loss, where amplification cannot recruit enough
residual hearing. Nothing addresses the connexin defect; this restores input around
it. Outcomes in GJB2-related hearing loss are good because the lesion is confined to
the cochlea and the auditory nerve the implant stimulates is intact.
treatment_term:
preferred_term: therapeutic procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:20301449
reference_title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
Because children with severe-to-profound hearing loss who are candidates for
cochlear implantation can attain levels of social functioning and education
indistinguishable from those of normal-hearing peers, cochlear implantation
should be performed as soon as possible.
explanation: >-
Gives the management standard for GJB2-related hearing loss. INDIRECT: the
chapter addresses the recessive form, and the recommendation is carried over on
the basis that the cochlear lesion and the implant candidacy are the same.
- name: AAV-Delivered Adenine Base Editing
therapeutic_modality: GENE_EDITING
description: >-
The most advanced experimental approach aimed at the actual lesion, and the one
whose logic fits this disease best. R75W is a single C-to-T substitution, so an
adenine base editor can revert it; an all-in-one AAV carrying a compact editor and
a guide corrected the mutation and restored the fragmented gap-junction plaques to
orderly outlines in cochlear supporting cells of a R75W transgenic mouse.
Two limits on reading this as a therapy for DFNA3A. It is preclinical - no human
GJB2 gene-therapy trial exists - and the mouse it was tested in is described by
that paper as a model of *syndromic* R75W disease with palmoplantar keratoderma,
while the paper that created the same allele's mouse describes the human family as
nonsyndromic. Restoring plaque morphology is also not the same as restoring
hearing, and the timing problem is unaddressed: the lesion here is a developmental
failure of the organ of Corti, so an editor delivered after that window may find
nothing left to rescue.
treatment_term:
preferred_term: Gene Therapy
term:
id: NCIT:C15238
label: Gene Therapy
target_mechanisms:
- target: Dominant-Negative Degradation of Connexin 26 Channels
description: >-
Reverting the mutant base removes the poison subunit, so channels assembled from
the remaining wild-type protein can dock normally again.
evidence:
- reference: PMID:40059830
reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base
editing also restored the fragmented GJPs to orderly outlines in cochlear
supporting cells.
explanation: >-
Shows the intervention acts on the structure this link targets - the gap
junction plaques in the supporting cells.
evidence:
- reference: PMID:40059830
reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
Our findings suggest that an ABE-based base-editing strategy could be an optimal
treatment for the dominant form of GJB2-related hearing loss, GJB2-related skin
diseases, and other deafness-related mutations, especially single-base
substitutions.
explanation: >-
The authors' own framing of the approach's scope. INDIRECT because it is a
forward-looking claim about a preclinical result, and because the model is
described there as syndromic.
- name: Allele-Specific Small Interfering RNA
therapeutic_modality: SIRNA
description: >-
Curated as an emerging strategy with a mechanistic rationale specific to this class
of disease, not as an available treatment. A dominant-negative allele is the ideal
target for allele-selective silencing, because removing the mutant transcript
restores the wild-type allele's channels rather than merely halving an already
reduced dose - which is precisely why this approach would not help DFNB1. Proof of
concept exists in patient keratinocytes for the dominant GJB2 allele that causes
keratitis-ichthyosis-deafness syndrome. It has not been attempted for a DFNA3A
allele, and delivery to the cochlear supporting-cell network is unaddressed.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:31705875
reference_title: Allele-Specific Small Interfering RNA Corrects Aberrant Cellular Phenotype in Keratitis-Ichthyosis-Deafness Syndrome Keratinocytes.
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: >-
In vitro treatment with allele-specific small interfering RNA led to robust
inhibition of the mutant GJB2 allele without altering expression of the wild-type
allele.
explanation: >-
Demonstrates selective knockdown of a mutant GJB2 allele, which is the mechanism
this treatment entry proposes. INDIRECT on two counts: the allele is a syndromic
one and the cells are keratinocytes, not cochlear.
animal_models:
- name: R75W dominant-negative connexin 26 transgenic mouse
species: Mouse
genotype: Transgenic for human GJB2 carrying the R75W dominant-negative allele
publication: PMID:12700168
description: >-
The workhorse model for dominant GJB2 disease, created because Gjb2 knockout mice
are embryonic lethal and so cannot be used to study hearing. Two independent lines
were established. Note that later work on the same allele describes it as causing
syndromic disease with palmoplantar keratoderma, while the founding paper describes
the human family as nonsyndromic - so its status as a DFNA3A model rests on the
original clinical description.
modeled_mechanisms:
- target: Failure of Organ of Corti Maturation
relationship: RECAPITULATES
fidelity: HIGH
description: >-
The mouse reproduces the developmental supporting-cell lesion in detail - absent
tunnel of Corti and Nuel's space, too few microtubules in inner pillar cells, a
short organ of Corti - and profound deafness from birth.
limitations: >-
A transgene expressing the mutant allele from a non-native promoter is not the
same as one mutant allele expressed from its own locus alongside a wild-type
partner, so the mutant-to-wild-type ratio is not physiological. The human disease
is also not uniformly congenital and profound, whereas the mouse never shows an
auditory brainstem response at any age.
readouts:
- name: Organ of Corti architecture at P5-P14
target: Failure of Organ of Corti Maturation
direction: ALTERED
interpretation: >-
Absent tunnel of Corti, Nuel's space and peri-outer-hair-cell spaces on
postnatal histology.
evidence:
- reference: PMID:18793701
reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histological observations at postnatal days (P) 5-14 were characterized by i)
absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair
cells
explanation: >-
The histological measurement behind this readout.
- name: Distortion product otoacoustic emissions
target: Failure of Organ of Corti Maturation
direction: ABOLISHED
interpretation: >-
Outer hair cell function is absent in vivo despite structurally and
electromotively normal outer hair cells, which is the functional signature of
scaffold failure rather than of hair cell disease.
evidence:
- reference: PMID:19712724
reference_title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
No detectable distortion product otoacoustic emissions were observed at any
frequencies in R75W transgenic mice throughout development.
explanation: >-
Reports the absent emissions across development.
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We established two lines of transgenic mice that showed severe to profound
hearing loss, deformity of supporting cells, failure in the formation of the
tunnel of Corti and degeneration of sensory hair cells.
explanation: >-
Supports treating this mouse as informative for the organ of Corti maturation
node.
- target: Cortilymph Potassium Homeostasis Disruption
relationship: FAILS_TO_RECAPITULATE
fidelity: MODERATE
description: >-
Recorded as a failure to recapitulate the *endolymphatic* potassium lesion that
the standard account of GJB2 deafness predicts. The mouse sustains a normal
endocochlear potential and has a structurally normal stria vascularis, so it does
not reproduce that mechanism - which is precisely its value, since it is what
relocated the potassium defect to cortilymph.
limitations: >-
The negative is a mouse negative. Species differences in cochlear connexin
expression are real, and the authors themselves hedge the extrapolation to
humans. The cortilymph account that replaces it was not measured directly either;
it is inferred from a preserved endocochlear potential together with a
degenerating organ of Corti.
readouts:
- name: Endocochlear resting potential
target: Cortilymph Potassium Homeostasis Disruption
direction: UNCHANGED
interpretation: >-
Normal endolymphatic resting potential, so the endocochlear potential is not the
failing step.
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The high resting potential in cochlear endolymph essential for hair cell
excitation was normally sustained.
explanation: >-
The measurement itself, reported as normal.
evidence:
- reference: PMID:12700168
reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Despite robust expression of the transgene, no obvious structural change was
observed in the stria vascularis or spiral ligament that is rich in connexin26
and generates the endolymph.
explanation: >-
Supports the negative claim: the compartment that generates endolymph is
structurally spared despite the transgene being expressed there.
discussions:
- discussion_id: dfna3a_dominant_allele_mechanism_heterogeneity
kind: KNOWLEDGE_GAP
prompt: >-
Do all DFNA3A alleles act by dominant negative interference, or do some act by
another route?
attaches_to:
- pathophysiology#Heterozygous GJB2 Variant Producing an Assembly-Competent Mutant Subunit
- pathophysiology#Dominant-Negative Degradation of Connexin 26 Channels
rationale: >-
The dominant-negative mechanism is demonstrated for W44C and assumed for the rest.
That assumption is uncomfortable for at least one reported dominant allele: the
299-300delAT frameshift truncates the protein, and a truncated subunit is a poor
candidate for poisoning a hexamer it may never join. Alternative routes are
available in principle - haploinsufficiency at a dosage-sensitive step, or aberrant
hemichannel activity of the kind demonstrated for the syndromic alleles. The
distinction is not academic: allele-selective silencing, curated above as a
treatment, works only against a dominant-negative or gain-of-function allele and
would make a haploinsufficiency allele worse.
- discussion_id: dfna3a_coupling_never_measured_in_disease
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Is loss of supporting-cell coupling the step that fails in DFNA3A, given that
coupling has never been measured in a cochlea carrying a DFNA3A allele?
attaches_to:
- pathophysiology#Loss of Cochlear Supporting-Cell Coupling
- pathophysiology#Cortilymph Potassium Homeostasis Disruption
rationale: >-
Three model systems each supply a different piece and none supplies the whole. The
dominant-negative effect is measured in Xenopus oocytes and HeLa cells at
experimenter-chosen expression ratios, in a system containing only connexin 26 -
whereas cochlear supporting cells co-express connexin 30, with which connexin 26
forms heteromeric channels. The dissociation of biochemical from electrical
coupling is measured in a connexin 30 knock-in mouse, a different gene. The
developmental scaffold failure is measured in a connexin 26 transgenic mouse that
over-expresses the mutant from a non-native promoter. So coupling itself has never
been measured in a system carrying a DFNA3A genotype at native stoichiometry.
This is a mismatch rather than an absence of evidence: each result is clean, and
each was generated in a system that omits the feature the next one shows to matter.
proposed_experiments:
- experiment_id: dfna3a_cx26_cx30_coexpression
name: Dominant allele co-expressed with connexin 30 at native ratios
description: >-
Repeat the co-expression conductance and dye-transfer assays with wild-type
connexin 26, a DFNA3A allele, and connexin 30 together, at expression ratios
measured from cochlear supporting cells rather than chosen by the experimenter,
and read out biochemical as well as electrical coupling.
would_support:
- pathophysiology#Loss of Cochlear Supporting-Cell Coupling
supporting_outcome:
- >-
Coupling is still substantially reduced when connexin 30 is present at native
ratios, so the effect survives the condition that most plausibly rescues it.
would_refute:
- pathophysiology#Loss of Cochlear Supporting-Cell Coupling
refuting_outcome:
- >-
Connexin 30 compensates and coupling is near normal, in which case the deafness
requires a mechanism other than lost coupling - most likely the altered docking
and gating already visible in the R75W hemichannel work.
- discussion_id: dfna3a_developmental_window_for_therapy
kind: KNOWLEDGE_GAP
prompt: >-
Is there a post-natal window in which correcting the GJB2 allele could still
restore hearing, or is the organ of Corti already malformed by then?
attaches_to:
- pathophysiology#Failure of Organ of Corti Maturation
- treatments#AAV-Delivered Adenine Base Editing
rationale: >-
The base-editing result restores gap junction plaque morphology in supporting
cells, but the lesion this entry models is a failure of the organ of Corti to form
in the first place - absent tunnel of Corti, absent Nuel's space - which is
complete by around P14 in the mouse. Restoring the protein after the scaffold has
failed to develop may restore the junctions without restoring hearing, and no
hearing outcome has been reported for the edited animals. The gap is the single
most consequential unknown for whether this class of therapy can work in this
disease, and it is a different question from whether the editing is efficient.
references:
- reference: PMID:20301449
title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss.
tags:
- GeneReviews
- reference: PMID:9139825
title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
- reference: PMID:12064630
title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
- reference: PMID:16009703
title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
- reference: PMID:12700168
title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
- reference: PMID:18793701
title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
- reference: PMID:19712724
title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
- reference: PMID:20858605
title: The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.
- reference: PMID:9529365
title: Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.
- reference: PMID:21484990
title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
- reference: PMID:22547955
title: GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss.
- reference: PMID:12522692
title: "Connexin26 gene ( GJB2): prevalence of mutations in the Chinese population."
- reference: PMID:12768774
title: "[Mutations in the connexin 26 gene in patients with nonsyndromic hearing impairment]."
- reference: PMID:22695344
title: The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study.
- reference: PMID:10369869
title: "A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families."
- reference: PMID:25625422
title: "Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43."
- reference: PMID:31705875
title: Allele-Specific Small Interfering RNA Corrects Aberrant Cellular Phenotype in Keratitis-Ichthyosis-Deafness Syndrome Keratinocytes.
- reference: PMID:33443819
title: Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
- reference: PMID:40059830
title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
notes: >-
Lump/split decision. DFNA3A is curated as its own Disease entry rather than as a
has_subtypes entry on a GJB2 or nonsyndromic-hearing-loss parent. It holds its own
MONDO term, and the mechanism is genuinely different from the recessive form at the
same locus rather than a milder or more severe version of it: DFNB1 is biallelic loss
of function, DFNA3A is a single allele acting on its wild-type partner. The KB already
curates the dominant *syndromic* connexin 26 disorders separately
(Keratoderma_Hereditarium_Mutilans) and carries GJB2-GJB6_Digenic_Nonsyndromic_Hearing_Loss;
this entry completes the set with the dominant nonsyndromic form.
Naming. MONDO's label is "autosomal dominant nonsyndromic hearing loss 3A" and the
entry uses it. DFNA3 was later split into DFNA3A (GJB2) and DFNA3B (GJB6); older
literature says only "DFNA3" and the reader has to infer the gene. Every source cited
here that says DFNA3 is doing so about GJB2, which is why the synonyms retain the
unsuffixed forms.
A correction worth recording, because the first draft of this entry had it wrong. The
standard account of GJB2 deafness is failure of endolymphatic potassium recycling and
the endocochlear potential, and this entry was originally modelled that way. The
dominant-negative mouse says otherwise: the endocochlear potential is normally
sustained and the stria vascularis is structurally intact, while the organ of Corti
fails to form its tunnel and its extracellular spaces. The potassium node was
therefore relocated to cortilymph - the space immediately around the hair cells - and
the normal endocochlear potential is curated as a REFUTE item against the endolymph
account rather than quietly dropped. The primary lesion in this entry is now a
developmental failure of the supporting-cell scaffold, with hair cell loss downstream
of it.
Evidence base and its limits, stated plainly. There is no DFNA3A cohort, no
audiological series, no natural history and no prevalence estimate - so there is no
prevalence block, and the frequency values on the phenotypes are structural (OBLIGATE
for the defining feature) rather than measured. The human evidence is a handful of
pedigrees. Everything mechanistic is model-system evidence, and the three systems do
not overlap: heterologous expression for the channel defect, a connexin 30 knock-in
mouse for the biochemical-coupling dissociation, and a connexin 26 transgenic mouse
for the developmental lesion. The two nodes where no measurement exists at a DFNA3A
genotype are PROVISIONAL, and the mismatch is filed as a discussion rather than
papered over. Several items are graded IN_VITRO or MODEL_ORGANISM where a reader might
expect HUMAN_CLINICAL: that is deliberate and follows the KB rule that evidence_source
describes the cited study.
A disagreement in the literature, left standing rather than resolved. The R75W allele
is the one most of the mechanistic work in this entry uses. Kudo and colleagues
identified it in a family with autosomal dominant *nonsyndromic* deafness and titled
their paper accordingly; the 2025 base-editing paper working on the same allele calls
it a cause of *syndromic* hearing loss with palmoplantar keratoderma. Both statements
are curated where they appear rather than one being suppressed, and the animal model's
description says so, because the disagreement bears directly on whether the R75W mouse
is a model of this entry or of a neighbouring one.
Named-entity-confusion check. Four traps at this locus. DFNA3A (GJB2) is not DFNA3B
(GJB6). DFNA3A is not DFNB1, though the gene is the same. Dominant GJB2 disease is
more often syndromic than not, so a dominant GJB2 pedigree is not automatically
DFNA3A. And M34T/101T>C appears in the literature as a DFNA3 allele but was shown not
to be sufficient to cause hearing loss; that refutation is curated rather than
silently dropped, precisely so the retracted assignment is not re-imported by a future
curator reading the older paper.
DFNA3A maps to the DFNA3 locus at chromosome 13q12.11 and is caused by heterozygous variants in GJB2, which encodes connexin 26. The defining molecular feature that distinguishes the rare dominant DFNA3A form from the common recessive DFNB1A form is the dominant-negative behavior of the mutant protein. In Xenopus oocyte co-expression assays, the dominant mutant W44C "dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties" (PMID: 12064630) — the hallmark of a poison-subunit effect on the wild-type allele. By contrast, recessive mutants such as W77R do not interfere with wild-type channels.
A parallel mechanistic dissection of the R75W mutant showed that its dominance emerges specifically at the level of gap-junction channel assembly: "The R75W phenotype is dominant at the gap-junction channel but not at the hemichannel level" (PMID: 16009703). Beyond missense alleles, a heterozygous frameshift also causes dominant disease: "Heterozygous deletion AT at position 299-300 of Cx26 cDNA can lead to autosomal dominant hereditary hearing loss (DFNA3)" (PMID: 12768774).
Interpretation: Dominance in DFNA3A is not simple haploinsufficiency; it requires the mutant subunit to be expressed, oligomerize with wild-type Cx26, and suppress or corrupt the function of the resulting mixed channels.
Transgenic mice expressing the dominant-negative human Cx26 R75W allele recapitulate the human disease and reveal where the lesion falls. Two independent transgenic lines "showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells" (PMID: 12700168). Postnatal histology (P5–P14) confirmed a developmental supporting-cell defect: "absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells" (PMID: 18793701).
Importantly, the defect is restricted to the non-sensory supporting cells. The stria vascularis and the endocochlear potential are preserved: "The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained" (PMID: 12700168). Outer hair cells themselves develop normally and retain their electromotile machinery (non-linear capacitance and prestin), yet distortion-product otoacoustic emissions are absent because the surrounding supporting-cell architecture is malformed (PMID: 19712724).
Interpretation: The primary pathology is a developmental failure of the supporting-cell scaffold of the organ of Corti, with hair-cell degeneration as a secondary, downstream consequence. This places the causal lesion in cortilymph/supporting-cell homeostasis, not endolymph generation.
The same gene, and sometimes the same codon, produces a spectrum ranging from isolated hearing loss to skin-plus-deafness syndromes. Dominant GJB2 variants cause palmoplantar keratoderma (PPK) with deafness, keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210; commonly p.D50N), Vohwinkel syndrome (mutilating PPK; p.G59S), and Bart-Pumphrey syndrome, in addition to nonsyndromic DFNA3A. A useful mechanistic dichotomy has been proposed: "Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function" (PMID: 22547955) — i.e., aberrant/leaky hemichannel activity underlies the skin phenotypes.
That a single dominant variant class can produce either outcome is illustrated by a report of "three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss" (PMID: 29575629). The R75W allele itself, dominant-negative for hearing, can also present syndromically: "Dominant-negative mutations of GJB2, such as R75W, cause syndromic hearing loss and palmoplantar keratoderma" (PMID: 40059830).
Interpretation: DFNA3A sits on a phenotypic continuum with dominant syndromic Cx26 disease. Whether a dominant allele manifests as isolated deafness or deafness-plus-skin disease depends on the balance between loss of gap-junction coupling (deafness) and gain of pathological hemichannel activity (skin/epidermal disease).
A novel dominant p.D46N missense variant caused DFNA3A in two Iranian families ascertained "from the same village in northern Iran consistent with a founder effect" (PMID: 21484990), demonstrating that regional founder alleles occur even in this rare dominant subset. A large systematic review integrating natural history and genotype–phenotype data across recessive, dominant, and digenic GJB2 forms underscores that "GJB2-related hearing loss is the most common type of hereditary hearing loss worldwide" (PMID: 41690513) — the epidemiological backdrop against which DFNA3A is a minority dominant contributor. On the therapeutic front, an all-in-one AAV adenine base editor corrected the R75W mutation, and "AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells" (PMID: 40059830).
Structural and cysteine-scanning studies map the first extracellular loop (E1, residues ~42–51) of Cx26 to a pore-lining "parahelix" (a 3₁₀ helix) that forms the narrowest, gating-critical region of the channel. During loop-gating the pore contracts dramatically, and "the largest conformational change occurs in the most stable region of the channel pore, the 3(10) or parahelix formed by amino acids in the 42-51 segment" (PMID: 21978595). This E1 region also governs channel selectivity: "a single residue difference in their E1 domains can largely account for their differential permeabilities to anionic tracers" (PMID: 39302317), comparing Cx26 (Ala at position 49) with Cx30 (Glu).
Many dominant DFNA3A missense variants — W44C/S/G, D46N, and residues near positions 49/55 — localize to precisely this E1 pore-lining/docking segment. Their position explains why they are dominant rather than null: rather than merely failing to form channels, they co-assemble into mixed channels and alter the gating and permeability of the resulting heteromeric pores.
Interpretation: The E1 parahelix is a mechanistic "hot zone." Mutations here do not simply delete a subunit; they change the biophysical behavior of channels that still contain wild-type subunits — the structural basis of dominant negativity.
A knock-in mouse carrying the human deafness-associated Cx30 T5M mutation (a paralogous DFNA3B/GJB6 model) is highly instructive because it dissociates the two types of intercellular coupling. These mice had only mild (~15 dB) threshold elevation, and "In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced" — along with reduced IP₃-evoked Ca²⁺ signaling and down-regulated Cx26/Cx30 (PMID: 20858605). Complementary work establishes the developmental purinergic system that this coupling serves: cochlear supporting cells use an ATP–Ca²⁺ signaling network linking "ATP release, Ca(2+) signaling, the expression and function of gap junction proteins connexin26 and connexin30, and the acquisition of hearing" (PMID: 23022499).
Interpretation: Loss of biochemical/second-messenger coupling (Ca²⁺, IP₃, ATP) among supporting cells is by itself sufficient to impair hearing, independent of, or in addition to, any defect in K⁺ recycling. This modernizes the classic "potassium recycling" model of connexin deafness.
Inner-ear gene therapy has achieved clinical proof-of-concept, but for a different gene: "eight clinical trials targeting DFNB9 have been registered in 51 centers across eight countries, demonstrating the rapid progress of gene therapy in auditory medicine" (PMID: 40908193) — these target OTOF-related recessive deafness 9. The broader molecular toolkit for sensorineural hearing loss now includes "gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing" (PMID: 31227837). For GJB2/DFNA3A specifically, therapy remains at the animal-model stage (the AAV base-editing R75W correction of PMID: 40059830); no human GJB2 gene-therapy trial has been reported.
DFNA3A is a rare Mendelian, autosomal dominant, nonsyndromic (isolated) sensorineural hearing loss. It is the dominant counterpart of the far more common recessive GJB2 deafness (DFNB1A).
| Identifier type | Value |
|---|---|
| OMIM (phenotype) | #601544 (DEAFNESS, AUTOSOMAL DOMINANT 3A; DFNA3A) |
| Gene / OMIM (gene) | GJB2 / 121011 |
| HGNC | HGNC:4284 (GJB2) |
| Locus | 13q12.11 (DFNA3 locus) |
| Suggested MONDO | MONDO:0011152 |
| ICD-10 | H90.5 (sensorineural hearing loss, unspecified) |
| ICD-11 | AB52 (sensorineural hearing impairment) |
| MeSH | Connexin 26 / GJB2; "Deafness, Autosomal Dominant" |
Synonyms / alternative names: DFNA3A; autosomal dominant deafness 3A; nonsyndromic hearing loss and deafness, DFNA3; connexin 26-related autosomal dominant deafness. The historical "DFNA3" locus was split into DFNA3A (GJB2) and DFNA3B (GJB6/Cx30).
Source of information: Predominantly aggregated disease-level resources (OMIM, ClinVar, systematic reviews) supplemented by individual family/case reports and functional/animal studies; not derived from a single EHR cohort.
The core phenotype is bilateral sensorineural hearing loss (HPO HP:0000407, sensorineural hearing impairment; HP:0000365, hearing impairment). Characteristics inferred from the DFNA3A family reports and the GJB2-hearing-loss literature:
| Attribute | DFNA3A characterization | HPO term |
|---|---|---|
| Onset | Congenital to early-childhood; some dominant families later-onset/progressive | HP:0008527 (congenital SNHL); HP:0000408 (progressive SNHL) |
| Severity | Moderate to profound; variable | HP:0000407 |
| Progression | Often stable but can be progressive | HP:0000408 |
| Laterality | Bilateral (occasionally asymmetric in syndromic overlap) | HP:0008619 (bilateral SNHL) |
| Frequency among carriers | High penetrance for hearing loss in reported dominant pedigrees | — |
Because DFNA3A is nonsyndromic by definition, there are no associated skin, eye, or systemic features; when skin (PPK), corneal (keratitis), or nail findings appear, the diagnosis shifts to the syndromic Cx26 disorders (KID, Vohwinkel, Bart-Pumphrey) discussed in F003.
Quality-of-life impact: Congenital/prelingual hearing loss impairs language acquisition, education, and social communication; this is the primary QoL burden and the rationale for early identification and cochlear implantation. No DFNA3A-specific EQ-5D/SF-36 dataset is available.
DFNA3A is a monogenic, environment-independent disorder. No toxins, occupational exposures, lifestyle factors, or infectious agents are implicated in its causation. (Environmental exposures such as noise or ototoxic aminoglycosides could additively worsen any pre-existing hearing loss, but they are not part of DFNA3A etiology.)
Causal chain (upstream → downstream):
Heterozygous dominant GJB2 variant (e.g., R75W, W44C; E1 parahelix)
│
▼
Mutant Cx26 subunit oligomerizes with wild-type Cx26
│ (dominant-negative: poisons mixed hexamers/dodecamers)
▼
Cochlear supporting-cell gap junctions fail / gate abnormally
• Loss of biochemical coupling: Ca²⁺, IP₃, ATP (purinergic) ← primary
• Impaired K⁺ recycling ← contributory
│
▼
Failure of organ-of-Corti maturation
(no tunnel of Corti / Nuel's space; deformed pillar & Deiters cells)
│
▼
Secondary sensory hair-cell degeneration (OHC develop but degenerate)
│ [Endocochlear potential & stria vascularis PRESERVED]
▼
Bilateral sensorineural hearing loss (DFNA3A)
There is no disease-modifying pharmacotherapy for DFNA3A. Management is habilitative:
| Modality | Detail | NCIT suggestion |
|---|---|---|
| Hearing aids | First-line amplification for mild–moderate loss | NCIT:C50071 (Hearing Aid) |
| Cochlear implantation | Standard of care for severe–profound loss; favorable in GJB2 | NCIT:C15845 (Cochlear Implant procedure) |
| Speech/language therapy & auditory rehabilitation | Maximizes language outcomes post-device | — |
| Genetic counseling | Dominant (50%) recurrence risk; cascade testing | — |
| Experimental — gene/base editing | AAV adenine base editing corrected R75W and restored cochlear GJ plaques in mice — preclinical only (PMID: 40059830) | NCIT:C16410 (Gene Therapy) |
| Experimental — antibody modulation | Human monoclonal antibody modulating mutant Cx26 hemichannels (relevant to syndromic gain-of-function) (PMID: 29018324) | — |
Because dominant alleles are toxic (dominant-negative/gain-of-function), the rational precision strategy is allele-specific correction or knockdown (base/prime editing, allele-selective ASO/siRNA) rather than gene addition — a modality still in the animal-model stage (PMID: 40059830, PMID: 31227837).
| Model | Type | Key phenotype | Recapitulation | PMID |
|---|---|---|---|---|
| Transgenic human Cx26 R75W mouse | Dominant-negative transgenic | Severe–profound deafness; no tunnel of Corti; supporting-cell deformity; secondary hair-cell loss; normal EP | High for DFNA3A supporting-cell mechanism | 12700168, 18793701, 19712724 |
| Round-window R75W delivery (mouse) | In vivo transient expression | Reversible hearing loss confirming dominant-negative action in mature cochlea | Functional confirmation | 17462767 |
| Conditional Gjb2-null mouse | Knockout | Immature (closed) tunnel of Corti; deafness not rescued by Cx30 overexpression | Establishes Cx26's non-redundant developmental role | 22142852 |
| Cx30 T5M knock-in mouse | Knock-in (paralog, DFNA3B model) | Mild ~15 dB loss; normal electrical but reduced biochemical (Ca²⁺/calcein) coupling | Models biochemical-coupling mechanism | 20858605 |
| In vitro: Xenopus oocytes, rat keratinocytes | Cellular / electrophysiology | Dominant-negative conductance suppression; ER retention/trafficking defects | Mechanistic dissection of specific alleles | 12064630, 16009703, 33443819 |
Model limitation: The R75W transgenic overexpresses the mutant and produces a more profound, developmental phenotype than some human DFNA3A families; humanized knock-in models at endogenous expression would better match variable human severity.
DFNA3A is fundamentally a disorder of intercellular communication in the cochlear supporting-cell syncytium. A single heterozygous dominant GJB2 allele encodes a Cx26 subunit that is not silent but actively corrupts the channels it joins. Because gap-junction channels are hexameric connexons that dock in pairs, one mutant subunit can disable an entire dodecameric channel — the structural basis of dominance, and the reason DFNA3A behaves so differently from recessive DFNB1A even though both involve the same gene.
The functional lesion is best understood as loss of biochemical coupling (Ca²⁺, IP₃, ATP-driven purinergic waves) among supporting cells during a critical postnatal developmental window, with impaired K⁺ recycling as a contributing but not exclusive factor. The downstream anatomical signature — failure to open the tunnel of Corti and to form the fluid spaces around the outer hair cells — reflects the developmental role of this signaling, and hair-cell degeneration follows as a secondary event. Preservation of the endocochlear potential firmly localizes the defect away from the stria vascularis and onto the organ-of-Corti support scaffold.
The E1 parahelix clustering of dominant alleles ties genotype to biophysics: these residues line the pore and drive loop-gating, so mutating them changes the permeability/gating of mixed wild-type/mutant channels rather than simply eliminating channels. The same gene's phenotypic breadth (isolated deafness ↔ skin-plus-deafness syndromes) is explained by a two-axis model: loss of gap-junction coupling → deafness, gain of aberrant hemichannel activity → epidermal disease.
| PMID | Contribution | Relationship to findings |
|---|---|---|
| 12064630 | W44C dominant-negative suppression of WT Cx26 | Supports F001 (dominant-negative mechanism) |
| 16009703 | R75W dominance at GJ-channel (not hemichannel) level | Supports F001 |
| 12768774 | Heterozygous c.299_300delAT causes dominant DFNA3 | Supports F001 (variant spectrum) |
| 12700168 | R75W transgenic mouse: supporting-cell/tunnel-of-Corti failure; EP preserved | Supports F002 |
| 18793701 | Postnatal absence of tunnel of Corti/Nuel's space | Supports F002 |
| 19712724 | OHC preserve non-linear capacitance despite absent DPOAE | Supports F002 |
| 22547955 | Nonsyndromic = LOF; syndromic = GOF dichotomy | Supports F003 |
| 29575629 | Novel dominant variants, syndromic + nonsyndromic | Supports F003 |
| 40059830 | R75W syndromic link; AAV base editing restores GJ plaques | Supports F003, F004, F007 |
| 21484990 | D46N founder effect (Iran) | Supports F004 |
| 41690513 | GJB2 most common hereditary hearing loss | Supports F004 |
| 21978595 | E1 42–51 parahelix is the pore-gating region | Supports F005 |
| 39302317 | Single E1 residue controls anionic permeability | Supports F005 |
| 20858605 | Cx30 T5M knock-in: normal electrical, reduced biochemical coupling | Supports F006 |
| 23022499 | ATP–Ca²⁺ purinergic signaling in developing cochlea | Supports F006 |
| 40908193 | OTOF (DFNB9) gene therapy in clinic | Supports F007 (contrast) |
| 31227837 | Molecular therapy toolkit for SNHL | Supports F007 |
Supporting/contextual: 17462767 (round-window R75W delivery), 22142852 (Cx26 non-redundant development), 25381570 ("not just K⁺ recycling" review), 33443819 (M34K ER retention), 24522190 (Cx30 mutant cellular pathologies), 29018324 (anti-Cx26 antibody), 12522692 (population allele spectrum).
Report compiled from a 5-iteration autonomous investigation: 7 confirmed findings, 43 papers reviewed. Evidence types span human clinical/family reports, mouse models (transgenic, knock-in, conditional knockout), in vitro electrophysiology and cell biology, and structural/computational studies.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 35 |
| Resolved | 35 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 35 |
| On topic | 25 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:21978595 (6 mentions) - Voltage-dependent conformational changes in connexin channels.Weighed against this report's own most characteristic terms: dominant, dfna3a, gjb2, loss, cx26, hearing, allele, gene, deafness, r75w, recessive, dominant-negative, variant, syndromic, cochlear, disease, cell, phenotype, developmental, supporting.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 25 |
| Resolved | 24 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 19 |
| Terms named correctly | 8 |
| Terms named as a different term | 8 |
| Terms whose name is worth a second look | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0011152 (2 mentions) - the report calls it "autosomal dominant nonsyndromic deafness 3A", "Suggested MONDO"; MONDO calls it PHGDH deficiencyHP:0000407 (2 mentions) - the report calls it "Moderate to profound; variable"; HP calls it Sensorineural hearing impairmentHP:0000408 (2 mentions) - the report calls it "Often stable but can be progressive"; HP calls it Progressive sensorineural hearing impairmentCL:0000855 (1 mention) - the report calls it "inner-ear supporting cell"; CL calls it sensory hair cellCL:0002355 (1 mention) - the report calls it "Deiters/pillar supporting cell lineage"; CL calls it primitive red blood cellNCIT:C50071 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it Mixer DeviceNCIT:C15845 (1 mention) - the report calls it "Cochlear Implant procedure"; NCIT calls it Protein/Amino Acid Nutrition Research, Non-AnimalNCIT:C16410 (1 mention) - the report calls it "Gene Therapy"; NCIT calls it CentrifugationThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0008619 (2 mentions) - the report calls it "bilateral SNHL", "Localization / laterality: Bilateral"; HP calls it Bilateral sensorineural hearing impairment**, and lists "Hearing loss, sensorineural, bilateral" among its other namesGO:0006874 (1 mention) - the report calls it "cellular calcium ion homeostasis"; GO calls it intracellular calcium ion homeostasis, and lists "cellular calcium ion homeostasis" among its other namesGO:0005922 (1 mention) - the report calls it "connexin complex / gap junction"; GO calls it connexin complexThe report gives these identifiers more than one name of its own:
MONDO:0011152 - called "autosomal dominant nonsyndromic deafness 3A", "Suggested MONDO"HP:0008619 - called "bilateral SNHL", "Localization / laterality:** Bilateral"