DFNB26 is prelingual, severe-to-profound, nonsyndromic sensorineural deafness caused by homozygosity for a hypomorphic missense variant, p.Gly116Glu, in the pleckstrin homology domain of GAB1 - the scaffold adapter that couples the MET/HGF receptor tyrosine kinase to its downstream effectors. The reason to curate this entry is not the gene. It is that DFNB26 is one of a handful of human Mendelian diseases with a mapped, cloned, dominant suppressor. In the consanguineous Pakistani kindred PK-2, eight affected individuals entered the original linkage calculation and seven further members homozygous for the DFNB26 haplotype hear normally - and the seven hear normally because they additionally carry one copy of p.Arg544Gln in METTL13, at the unlinked DFNM1 locus on 1q24. Complete suppression, not attenuation. The genotype that causes profound congenital deafness in one sibship is silent in the next. The mechanism is legible down to a single transcript. GAB1 p.Gly116Glu sits in the PH domain and reduces binding to PtdIns(3,4,5)P3 by about 42%, so the adapter is recruited to the membrane less efficiently rather than abolished - a hypomorph, which is what makes a deafness-only phenotype possible at all, since complete loss of the GAB1 PH domain is embryonic lethal in mice and gab1 knockdown is lethal in zebrafish. Downstream, patient lymphoblastoid lines show broad dysregulation of MET/HGF pathway transcripts. Fourteen of them - thirteen down, PI3K up - move in deaf and non-penetrant homozygotes alike, so none of them can be what separates the two groups. Exactly one gene behaves differently: SPRY2 is significantly upregulated only in the deaf. METTL13 physically associates with both GAB1 and SPROUTY2 in a tripartite complex, so the suppressor and the one discriminating transcript sit in the same protein assembly. Where the lesion acts is unusual for a deafness gene: not in hair cells. A Gab1 LacZ reporter labels supporting cells of the organ of Corti, spiral ganglion neurons, stria vascularis, sulcus cells and Reissner's membrane, with no detectable signal in inner or outer hair cells; GAB1 and METTL13 colocalise in spiral ganglion neuronal cell bodies and in the fibres innervating the hair cells. DFNB26 is therefore better read as a neural/supporting-cell signalling disease than as a hair bundle disease. Two limits should be read alongside all of this. Everything above rests on one family, and the identification of GAB1 as the DFNB26 gene rests on segregation, exome sequencing that excluded intrafamilial heterogeneity, absence from population databases, and a biochemical lipid-binding deficit - not on an animal model of the human allele. And the "modifier" arm rests on the same family plus a zebrafish morphant rescue in which the suppressor allele partially rescued a developmental phenotype, not a hearing one.
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name: Autosomal Recessive Nonsyndromic Hearing Loss 26
category: Mendelian
creation_date: "2026-09-03T00:00:00Z"
synonyms:
- DFNB26
- deafness, autosomal recessive 26
- autosomal recessive deafness 26
- autosomal recessive nonsyndromic deafness 26
- autosomal recessive nonsyndromic deafness type 26
- GAB1-related nonsyndromic hearing loss
description: >-
DFNB26 is prelingual, severe-to-profound, nonsyndromic sensorineural deafness caused by
homozygosity for a hypomorphic missense variant, p.Gly116Glu, in the pleckstrin homology
domain of GAB1 - the scaffold adapter that couples the MET/HGF receptor tyrosine kinase
to its downstream effectors.
The reason to curate this entry is not the gene. It is that DFNB26 is one of a handful of
human Mendelian diseases with a mapped, cloned, dominant suppressor. In the consanguineous
Pakistani kindred PK-2, eight affected individuals entered the original linkage
calculation and seven further members homozygous for the DFNB26 haplotype hear normally -
and the seven hear normally because they additionally carry one copy of p.Arg544Gln in
METTL13, at the unlinked DFNM1 locus on 1q24. Complete suppression, not
attenuation. The genotype that causes profound congenital deafness in one sibship is
silent in the next.
The mechanism is legible down to a single transcript. GAB1 p.Gly116Glu sits in the PH
domain and reduces binding to PtdIns(3,4,5)P3 by about 42%, so the adapter is recruited to
the membrane less efficiently rather than abolished - a hypomorph, which is what makes a
deafness-only phenotype possible at all, since complete loss of the GAB1 PH domain is
embryonic lethal in mice and gab1 knockdown is lethal in zebrafish. Downstream, patient
lymphoblastoid lines show broad dysregulation of MET/HGF pathway transcripts. Fourteen of
them - thirteen down, PI3K up - move in deaf and non-penetrant homozygotes alike, so none
of them can be what separates the two groups. Exactly one gene behaves differently: SPRY2 is significantly
upregulated only in the deaf. METTL13 physically associates with both GAB1 and SPROUTY2 in
a tripartite complex, so the suppressor and the one discriminating transcript sit in the
same protein assembly.
Where the lesion acts is unusual for a deafness gene: not in hair cells. A Gab1 LacZ
reporter labels supporting cells of the organ of Corti, spiral ganglion neurons, stria
vascularis, sulcus cells and Reissner's membrane, with no detectable signal in inner or
outer hair cells; GAB1 and METTL13 colocalise in spiral ganglion neuronal cell bodies and
in the fibres innervating the hair cells. DFNB26 is therefore better read as a
neural/supporting-cell signalling disease than as a hair bundle disease.
Two limits should be read alongside all of this. Everything above rests on one family, and
the identification of GAB1 as the DFNB26 gene rests on segregation, exome sequencing that
excluded intrafamilial heterogeneity, absence from population databases, and a biochemical
lipid-binding deficit - not on an animal model of the human allele. And the "modifier"
arm rests on the same family plus a zebrafish morphant rescue in which the suppressor
allele partially rescued a developmental phenotype, not a hearing one.
disease_term:
preferred_term: autosomal recessive nonsyndromic hearing loss 26
term:
id: MONDO:0011553
label: autosomal recessive nonsyndromic hearing loss 26
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
references:
- reference: PMID:11101839
title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
- reference: PMID:29408807
title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
- reference: PMID:30143613
title: The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
- reference: PMID:30612740
title: METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
notes: >-
Literature base. A PubMed sweep run on 2026-09-04 covered GAB1 crossed with hearing loss
and deafness, DFNB26, DFNM1, METTL13, METTL13 crossed with deafness, and METTL13 crossed
with eEF1A. The two clinical papers on this disease remain the two cited here - no third
family and no independent replication has been published. The sweep did close a real gap
on the modifier side: METTL13's enzymatic activity, described as merely predicted in the
2018 JCI paper, was characterised later that same year (PMID:30143613) and independently
in 2019 (PMID:30612740), and both are now cited. PMID:39062623 (MAP3K1/DFNB128) surfaces
on a GAB1-deafness query but concerns a different locus and is not cited. A falcon
deep-research report was also generated and is committed at
research/Autosomal_Recessive_Nonsyndromic_Hearing_Loss_26-deep-research-falcon.md. No
curation was drawn from it, and its relevance profile says why: the validator scored only
1 of its 5 verified references as on topic. Five of its twelve numbered citations are the
same 2018 JCI paper already cited here as PMID:29408807; the remainder are adjacent-locus deafness
papers - Mujtaba 2015 on MET/DFNB97, Faridi 2024 on MAP3K1/DFNB128 (which is
PMID:39062623, the paper this sweep had already examined and declined), and the Naz and
Friedman growth-factor review - plus an Open Targets query. None reports on DFNB26. The
manual sweep therefore remains the working literature base for this entry, and the report
serves as a retrieval check that surfaced nothing it had missed.
Reference cache duplication. references_cache/DOI_10.1172_JCI97350.md and
references_cache/DOI_10.1172_jci97350.md are the same article in two DOI casings. Both
are present deliberately: the deep-research citation list emits the lowercase form and
the fetcher keys on the literal string, so removing either one would make reference
validation non-deterministic. This is not a stray duplicate.
GeneReviews. PMID:20301607, the Genetic Hearing Loss Overview, is cached and is tagged
GeneReviews in four sibling hearing-loss entries (ADNSHL_41, Auditory_Neuropathy,
COL11A2_Hearing_Loss and X-linked_Nonsyndromic_Hearing_Loss), but it is deliberately not
tagged here. Its cached record is abstract-only - the body is the chapter's six-point
statement of scope and nothing more - and contains no occurrence of GAB1, METTL13,
DFNB26 or DFNM1, so tagging it would produce a tagged-but-not-mined reference. There is
no GAB1-specific GeneReviews chapter. This paragraph records the negative so it is
auditable rather than looking like an omission, following the pattern in
kb/disorders/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_2B.yaml.
inheritance:
- name: Autosomal recessive
description: >-
Homozygosity for GAB1 c.347G>A (p.Gly116Glu) in a consanguineous Pakistani family, with
linkage to 4q31 reaching a LOD of 8.10 when only affected individuals were counted.
Heterozygotes are unaffected and no carrier of the allele was found in 380 Pakistani or
192 Indian control chromosomes, or in 1000 Genomes, NHLBI-ESP or ExAC.
penetrance: INCOMPLETE
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we map a new recessive nonsyndromic deafness locus, DFNB26, to a 1.5-cM interval of chromosome 4q31 in a consanguineous Pakistani family."
explanation: The original recessive mapping that defines the locus.
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A maximum lod score of 8.10 at theta=0 was obtained with D4S1610 when only the 8 affected individuals in this family were included in the calculation."
explanation: The linkage statistic, and the qualifier that it counts affected individuals only.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Segregation analysis of each of these variants in their respective sibships revealed that only the c.347G>A change in GAB1 cosegregated with deafness within each sibship."
explanation: >-
Exome sequencing across six sibships found the GAB1 allele to be the only variant
cosegregating with deafness in every sibship, which excludes intrafamilial genetic
heterogeneity - the main alternative explanation for this pedigree's pattern.
- name: Dominant suppression by an unlinked modifier locus
description: >-
The penetrance of the recessive genotype is controlled by a second, unlinked locus.
Seven family members homozygous for the DFNB26 haplotype hear normally; each carries one
copy of METTL13 p.Arg544Gln at DFNM1 on 1q24, and every deaf family member is homozygous
for wild-type METTL13.
This is a modifier relationship, not digenic inheritance, and is deliberately not bound
to HP:0010984. Digenic inheritance means variants at two loci are jointly required to
produce the disease; here the GAB1 genotype alone is sufficient, and the second locus
subtracts the phenotype rather than contributing to it. Modelling it as digenic would
invert the direction of the second allele's effect.
penetrance: INCOMPLETE
evidence:
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are seven unaffected family members who are also homozygous for the DFNB26-linked haplotype and thus are non-penetrant."
explanation: The non-penetrance that the modifier locus was mapped to explain.
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A dominant modifier, DFNM1, that suppresses deafness in the 7 nonpenetrant individuals was mapped to a 5.6-cM region on chromosome 1q24 with a lod score of 4.31 at theta=0 for D1S2815."
explanation: The mapping of the suppressor to an unlinked locus.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all deaf individuals were homozygous for the WT allele of METTL13"
explanation: >-
The suppressor allele is absent from every deaf family member. The quote starts
mid-sentence because the cached full text is PDF-derived and the preceding clause -
that the allele cosegregated with the DFNM1-linked haplotype - is split across a
hyphenated line break; that half is quoted from the abstract in the METTL13 genetic
entry instead.
pathophysiology:
- name: GAB1 p.Gly116Glu Hypomorphic PH-Domain Variant
description: >-
GAB1 c.347G>A in constitutive exon 2 substitutes glutamate for a conserved glycine at
residue 116, inside the pleckstrin homology domain of the adapter. The allele is absent
from Pakistani and Indian control chromosomes and from 1000 Genomes, NHLBI-ESP and ExAC,
and eight in silico tools call it deleterious.
The important qualifier is that it is hypomorphic rather than null. Homozygous deletion
of the sequence encoding the GAB1 PH domain is embryonic lethal in mice, and gab1
knockdown produces severe developmental defects and lethality in zebrafish, so a
complete loss of function could not present as isolated deafness. Residual GAB1 activity
is what restricts the phenotype to the ear.
biological_scale: MOLECULAR
genes:
- preferred_term: GAB1
term:
id: hgnc:4066
label: GAB1
downstream:
- target: Reduced Phosphoinositide Binding by the GAB1 PH Domain
causal_link_type: DIRECT
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway."
explanation: The causal allele and the protein domain it hits.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No carriers of the c.347G>A variant were found among 380 control chromosomes from Pakistani individuals or in 192 normal-hearing individuals from India."
explanation: Population absence supporting pathogenicity of the allele.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "assay as well as the zebrafish rescue studies support the assumption that the p.(Gly116Glu) substitution of GAB1 retains a reduced level of function (hypomorphic variant) compared with WT GAB1, which may explain the restricted deafness phenotype segregating in family PK-2."
explanation: >-
Establishes the allele as hypomorphic and links that directly to why the phenotype is
confined to hearing. The quote opens at "assay" because the words before it,
"our biochemical lipid-binding", are split across a hyphenated line break in the
PDF-derived cache. Note that this one sentence is the authors' synthesis across two
study arms and names both; it is graded on the biochemical assay, which is the arm
that measures the allele's residual function directly. Both arms are also carried
separately and with their own grades elsewhere in this entry - the quantified
PIP-array result as IN_VITRO in this same node, and the zebrafish morphant rescue as
MODEL_ORGANISM under the METTL13 modifier - so no evidence is lost by leaving this
summary sentence unsplit, and there is no contiguous substring of it that carries the
hypomorphic conclusion without the cross-arm attribution.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "GAB1 is ubiquitously expressed, and in mice, a homozygous deletion of the sequence encoding the PH domain of GAB1 results in embryonic lethality between E12.5 and E18.5"
explanation: >-
The lethality of the null, which is the constraint that forces the human allele to be
hypomorphic.
- name: Reduced Phosphoinositide Binding by the GAB1 PH Domain
description: >-
The PH domain is how GAB1 reaches the membrane: it binds phosphoinositides, principally
PtdIns(3,4,5)P3, positioning the adapter where activated receptor tyrosine kinases can
phosphorylate it. In an overlay assay against a phosphoinositide array, the p.Gly116Glu
PH domain bound PtdIns(3,4,5)P3 about 42% less than wild type, with smaller reductions
against PtdIns(4,5)P2, PtdIns(3)P and PtdIns(4)P. The qualitative binding preference is
unchanged - it is the amount, not the specificity, that falls.
biological_scale: MOLECULAR
genes:
- preferred_term: GAB1
term:
id: hgnc:4066
label: GAB1
molecular_functions:
- preferred_term: phosphatidylinositol-3,4,5-trisphosphate binding
modifier: DECREASED
term:
id: GO:0005547
label: phosphatidylinositol-3,4,5-trisphosphate binding
- preferred_term: phosphatidylinositol binding
modifier: DECREASED
term:
id: GO:0035091
label: phosphatidylinositol binding
downstream:
- target: Dysregulated MET/HGF Signaling
causal_link_type: DIRECT
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "On average, a 42% (**P < 0.01) decrease in the binding of the mutant PH domain protein to PtdIns(3,4,5)P3 was observed, as well as reductions of 44%, 40%, and 30% (*P < 0.05) in binding to PtdIns(4,5)P2, PtdIns(3)P , and PtdIns(4)P , respectively."
explanation: The quantified lipid-binding deficit, the direct biochemical consequence of the allele.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "No difference was observed in the binding pattern of GAB1-PH domain harboring the p.Gly116Glu allele with PtdIns. However, p.Gly116Glu substitution reduced the binding of the PH domain to PtdIns(3,4,5)P3."
explanation: Specificity is preserved; affinity is not. That is the shape of a hypomorph.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
snippet: "Like other IRS1 adapter proteins, GAB1 has a PH domain that facilitates interaction with phosphatidylinositols within cell membranes and is involved in assembling complexes that function downstream of cell-surface RTKs"
explanation: >-
Why reduced phosphoinositide binding matters functionally. Graded OTHER because the
quoted sentence is background on the protein family rather than a result of this study.
- name: Dysregulated MET/HGF Signaling
description: >-
GAB1 is the adapter for MET, the hepatocyte growth factor receptor, and this pathway is
already established in human deafness from the other direction: noncoding HGF variants
cause DFNB39, a MET variant is associated with DFNB97, and SHP2 and SPRY2 deficits cause
hearing loss in humans and mice respectively.
In lymphoblastoid lines from family PK-2, 37 HGF-signaling genes were profiled. MET,
AKT3, hRAS, STAT1, FAS-R, RAC1, C3G, RAP-1a, GRB2, SHC, EGR1, JAK1 and ELK1 were all
down more than two-fold and PI3K was up - but in deaf and non-penetrant homozygotes
alike. That is the signature of the GAB1 genotype, and by construction it cannot be what
distinguishes the two clinical outcomes.
biological_scale: CELLULAR
biological_processes:
- preferred_term: hepatocyte growth factor receptor signaling pathway
modifier: DECREASED
term:
id: GO:0048012
label: hepatocyte growth factor receptor signaling pathway
genes:
- preferred_term: MET
term:
id: hgnc:7029
label: MET
- preferred_term: HGF
term:
id: hgnc:4893
label: HGF
downstream:
- target: SPRY2 Upregulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Spiral Ganglion Neuron and Cochlear Supporting Cell Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Among these genes, MET, AKT3, hRAS, STAT1, FAS-R, RAC1, C3G, RAP-1a, GRB2, SHC, EGR1, JAK1, and ELK1 were downregulated by more than 2-fold (P < 0.05) in both DFNB26 deaf and nonpenetrant individuals"
explanation: >-
Broad pathway dysregulation attributable to the GAB1 genotype, explicitly present in
both clinical groups.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness."
explanation: >-
The dysregulated genes are themselves deafness genes, which is what makes the pathway
readout mechanistically interpretable rather than incidental. Graded IN_VITRO, like
every other item quoting this experiment: the measurement is real-time PCR on
lymphoblastoid cell lines derived from family members, and cultured cells are
IN_VITRO regardless of donor.
- name: SPRY2 Upregulation
description: >-
Of the 37 MET/HGF pathway transcripts profiled, SPRY2 was the only one that differed
between deaf and non-penetrant homozygotes: significantly upregulated in the deaf, and
not upregulated in normal-hearing individuals carrying both the GAB1 variant and the
METTL13 suppressor. SPROUTY2 is a negative regulator within this pathway and its loss
causes hearing loss in mice, so a change in its level is a plausible effector rather
than a bystander.
The suppression acts here. METTL13 coimmunoprecipitates with both GAB1 and SPROUTY2 and
the three form a tripartite complex, so the modifier protein is physically positioned
where the one discriminating transcript is controlled. The authors describe this as a
plausible mechanism of suppression; whether normalising SPRY2 is what rescues hearing,
or is a marker of something else the complex does, is not established.
biological_scale: MOLECULAR
genes:
- preferred_term: SPRY2
term:
id: hgnc:11270
label: SPRY2
- preferred_term: METTL13
term:
id: hgnc:24248
label: METTL13
downstream:
- target: Spiral Ganglion Neuron and Cochlear Supporting Cell Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Intriguingly, SPRY2 was significantly (P < 0.001) upregulated only in the lymphoblastoid cell lines from the 3 deaf individuals of family PK-2."
explanation: >-
The single transcript that separates the deaf from the non-penetrant carriers of the
same GAB1 genotype.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression."
explanation: >-
The suppressed state of the same readout in the modifier-carrying individuals. The
subjects are people, but the measurement is the same lymphoblastoid cell line panel,
so this is IN_VITRO like the rest of that experiment.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These studies suggest that METTL13 interacts with both GAB1 and SPROUTY2 to form a tripartite complex."
explanation: >-
Physical association placing the modifier protein in the same complex as the
discriminating transcript's product.
- name: Spiral Ganglion Neuron and Cochlear Supporting Cell Dysfunction
description: >-
Where GAB1 is expressed in the inner ear constrains what kind of disease DFNB26 can be.
All of the expression data below are from mouse. A Gab1 LacZ reporter in mouse cochlea at
P0 labels supporting cells of the organ of Corti, spiral ganglion neurons, stria
vascularis, spiral prominence, internal and external sulcus cells, spiral limbus and
Reissner's membrane - and explicitly not the inner or outer hair cells. GAB1 and METTL13
colocalise with a neurofilament marker in mouse cochlear whole mounts, in spiral ganglion
neuronal cell bodies and in the fibres innervating the hair cells.
So the lesion is placed in the neural and supporting-cell compartment rather than in the
mechanotransduction apparatus. This is an expression-based inference: no cochlear
histology or physiology from a GAB1 p.Gly116Glu model has been reported, and the node
should be read as localising the pathway rather than as a demonstrated cellular
pathology.
biological_scale: CELLULAR
cell_types:
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
- preferred_term: organ of Corti supporting cell
term:
id: CL:0002490
label: organ of Corti supporting cell
downstream:
- target: Profound Prelingual Sensorineural Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "activity in the supporting cells of the organ of Corti (OC), spiral ganglion neurons (SG), internal (ISC) and external (ESC) sulcus cells, and spiral limbus region."
explanation: >-
The cell types labelled by the Gab1 LacZ reporter in whole-mount cochlea at P0 - the
supporting-cell and neuronal compartment, not the sensory hair cells.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "No detectable staining (see inset) was observed in inner (IHC) or outer (OHC) hair cells."
explanation: >-
The negative result that does the work here: the disease gene is not detectably
expressed in the cells that carry the mechanotransduction apparatus, which is why this
entry places the lesion outside them.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These data indicate that Gab1 and Mettl13 are expressed in the spiral ganglion, stria vascularis"
explanation: >-
The authors' summary of where both genes are expressed in the cochlea. Truncated after
the stria vascularis because the next list item, "spiral prominence", is split across a
hyphenated line break in the PDF-derived cache; the full list is given in this node's
description.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Spiral ganglion (bottom) revealed colocalization of GAB1, METTL13, and NF200 in the neuronal cell bodies (SGN) as well."
explanation: >-
Co-expression of the disease gene and its suppressor in the same neurons, which is what
makes the spiral ganglion the natural place to look for the lesion.
phenotypes:
- name: Profound Prelingual Sensorineural Hearing Loss
category: Auditory
description: >-
Severe-to-profound sensorineural hearing loss present before speech acquisition, without
extra-auditory features. Medical and developmental history, physical examination and
routine blood and urine chemistry in the affected individuals of family PK-2 revealed no
non-auditory findings, which is what establishes the entity as nonsyndromic rather than
as the ear component of a broader GAB1 phenotype.
frequency: OBLIGATE
phenotype_term:
preferred_term: Profound sensorineural hearing impairment
term:
id: HP:0011476
label: Profound sensorineural hearing impairment
notes: >-
Graded OBLIGATE as definitional rather than as a counted proportion. It is the phenotype
that defines an affected individual in the only reported family; homozygotes without it
are recorded as non-penetrant, and they are the subject of the modifier arm of this entry.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dominant modifier variant have prelingual, nonsyndromic severe-to-profound hearing loss"
explanation: >-
Severity, timing and the nonsyndromic character. The quote begins mid-sentence because
the subject clause - the deaf individuals homozygous for p.Gly116Glu who do not carry
the METTL13 modifier - runs across a hyphenated line break in the PDF-derived cache;
that clause is what "have" refers to.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "histories, physical examination, and routine blood and urine chemistry tests did not reveal any extra-auditory features in these affected individuals"
explanation: >-
The basis for calling the entity nonsyndromic. Opens at "histories" because the
preceding words, "Medical and developmental", are split across a hyphenated line break
in the cache.
- name: Prelingual Onset
category: Auditory
description: >-
Hearing loss is present before speech acquisition, in contrast to the postlingual,
progressive course typical of dominant nonsyndromic forms.
phenotype_term:
preferred_term: Prelingual sensorineural hearing impairment
term:
id: HP:0000399
label: Prelingual sensorineural hearing impairment
notes: >-
This entry is deliberately not wired into the causal graph and is deliberately not
folded into Profound Prelingual Sensorineural Hearing Loss as an onset descriptor.
It is not a separate consequence of any pathophysiology node - it is the timing axis of
the same clinical event - so there is no edge any source supports, and CLAUDE.md's rule
for that case is to leave it disconnected and say so here rather than invent one.
It is kept as its own phenotype only so that HP:0000399 stays queryable alongside the
severity term HP:0011476 on the main phenotype; a phenotype carries one term, so the two
axes cannot share an entry. Folding it into an onset: block instead would mean choosing
an OnsetEnum value, and both sources say only "prelingual", which does not distinguish
congenital from neonatal or infantile onset. Asserting CONGENITAL would be more specific
than the literature.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we provide evidence that a missense variant (c.347G>A (p.Gly116Glu)) in the PH domain of human GAB1 causes nonsyndromic, profound, prelingual"
explanation: >-
The authors' summary statement of the phenotype, including its prelingual onset.
Truncated before "sensorineural", which is split across a hyphenated line break in the
PDF-derived cache.
prevalence:
- population: Family PK-2, Pakistan
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
DFNB26 is described in a single consanguineous Pakistani kindred across the two reports
curated here: eight affected individuals entered the original linkage calculation, and a
further seven members homozygous for the DFNB26 haplotype are non-penetrant. No second
family with a GAB1 hearing-loss variant is cited in
either paper. Every clinical and mechanistic statement in this entry therefore derives
from one pedigree, which is why no phenotype frequency band is asserted from counts.
evidence:
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are seven unaffected family members who are also homozygous for the DFNB26-linked haplotype and thus are non-penetrant."
explanation: >-
The seven non-penetrant homozygotes of the only reported kindred. The affected count
is quoted separately from the same paper's linkage sentence, which states that eight
affected individuals were included in the calculation - not necessarily that eight is
the total number of affected members.
genetic:
- name: GAB1
notes: >-
GAB1 (4q31) encodes a member of the IRS1-like multisubstrate docking adapter family. It
carries a PH domain, a MET receptor-binding site, a central proline-rich region and
several phosphorylation sites, and it transmits signals from MET/HGF, IGF-1 and ErbB2
receptors to SHP2, PI3K and ERK. It is ubiquitously expressed; the null is embryonic
lethal in mice.
gene_term:
preferred_term: GAB1
term:
id: hgnc:4066
label: GAB1
relationship_type: CAUSATIVE
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
variants:
- name: c.347G>A (p.Gly116Glu)
description: >-
Homozygous missense substitution in constitutive exon 2, replacing a conserved glycine
in the PH domain. Predicted deleterious by all eight tools applied, absent from
population databases, and shown biochemically to reduce phosphoinositide binding.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A homozygous transition variant c.347G>A in exon 2 of GAB1 (NM_207123) was identified"
explanation: The causal variant as identified in the affected and non-penetrant individuals.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "We used 8 bioinformatics tools to evaluate functionality in silico, and all of them predicted that p.Gly116Glu is deleterious for GAB1 function"
explanation: In silico support for pathogenicity, unanimous across the tools applied.
- name: METTL13
notes: >-
METTL13 (1q24) sits at the DFNM1 locus. The disease-relevant allele is a heterozygous
dominant suppressor, not a cause: p.Arg544Gln, conserved across a wide range of species
and absent from Pakistani, Indian, Human Diversity Panel and 1000 Genomes controls.
The 2018 JCI paper that identified this allele describes METTL13's methyltransferase
and spermidine/spermine synthase activities as predicted only, and places p.Arg544Gln
in the "spermine/spermidine synthase domain". That was accurate when written and is no
longer the state of knowledge. METTL13 is a dual protein methyltransferase for
eukaryotic elongation factor 1A: its N-terminal domain (MT13-N) dimethylates eEF1A
Lys55, and its C-terminal domain (MT13-C) - the one that lacks close paralogs and is
distantly related to spermidine synthase, which is why the earlier annotation called it
an SpdS domain - trimethylates the eEF1A N terminus. The crystallised core of MT13-C
spans residues 470-699, so Arg544 falls inside it.
Two consequences for this entry. First, the suppressor allele now has a candidate
biochemical activity to act through, where in 2018 it had none. Second, the assignment
is specifically to the eEF1A N-terminal methyltransferase activity and not to the Lys55
activity: Liu et al. independently show that residues 1-401 suffice for Lys55
methylation and that the C-terminal domain is dispensable for it. What remains unknown
is whether the suppressor works through eEF1A methylation at all, and how any such
change would reach SPROUTY2 - see the knowledge gap below.
gene_term:
preferred_term: METTL13
term:
id: hgnc:24248
label: METTL13
relationship_type: MODIFIER
variants:
- name: c.1631G>A (p.Arg544Gln)
description: >-
Heterozygous dominant suppressor allele at DFNM1. Present in every non-penetrant
homozygote of family PK-2 and absent from every deaf member.
Nomenclature caution. PMID:29408807 is internally inconsistent about this variant. It
prints c.1631G>A eight times - in the Sanger sequencing results, in the Table 2
variant summary against NM_015935, and in the Figure 1E legend placing the change in
exon 6 - and c.1634G>A twice, in the zebrafish rescue narrative and once in the
discussion. This entry uses c.1631G>A throughout because that is the form the
sequence-level results and the variant table carry. A curator reading the paper will
hit the same fork; it is recorded here so it does not have to be re-derived.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness."
explanation: Identifies the modifier allele and its direction of effect.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The c.1631G>A variant is predicted to substitute a glutamine for a highly conserved arginine (p.Arg544Gln) in the"
explanation: >-
The variant and its conservation. The quote stops before the domain name, which is
followed by a figure callout in the cached text; the domain is named in this entry's notes.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype."
explanation: >-
In vivo functional support that the allele acts as a suppressor rather than merely
cosegregating with non-penetrance.
- reference: PMID:30143613
reference_title: The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively"
explanation: >-
METTL13's enzymatic activity is demonstrated, not merely predicted. Cited here to
correct the "predicted only" description carried over from the 2018 disease paper.
- reference: PMID:30143613
reference_title: The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the C-terminal domain (here denoted MT13-C) lacks close paralogs, but is distantly related to spermidine synthase (SpdS)"
explanation: >-
Identifies the domain the disease paper called a spermine/spermidine synthase domain,
which is the region p.Arg544Gln sits in, as MT13-C.
- reference: PMID:30143613
reference_title: The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "METTL13 is capable of methylating eEF1A in vitro and suggest that MT13-C targets the N terminus of eEF1A while MT13-N methylates a different site"
explanation: >-
Assigns the eEF1A N-terminal methyltransferase activity to MT13-C, the domain
containing Arg544, and the Lys55 activity to the other domain.
- reference: PMID:30612740
reference_title: METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In a screen of 107 potential KMTs, we identified METTL13 as an active enzyme that specifically di-methylates the elongation factor eEF1A at lysine 55."
explanation: Independent demonstration of METTL13 lysine methyltransferase activity on eEF1A.
- reference: PMID:30612740
reference_title: METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The N-terminal MTase 1 domain is necessary for METTL13 methylation of GST-eEF1AK55, whereas the C-terminal domain is dispensable for this activity"
explanation: >-
Locates the Lys55 activity away from the domain carrying p.Arg544Gln, which is why
this entry does not attribute the suppressor to the Lys55 activity.
diagnosis:
- name: Genotyping of the DFNM1 modifier alongside the GAB1 genotype
description: >-
In a family segregating the GAB1 allele, the GAB1 genotype alone does not predict
hearing status. A homozygote who also carries METTL13 p.Arg544Gln hears normally, so a
prediction of profound congenital deafness made from the GAB1 result by itself would be
wrong for all seven non-penetrant homozygotes of the only reported kindred. This is the practical
consequence of the modifier and the reason it belongs in the diagnostic workup rather
than only in the mechanism.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
snippet: "A modifier variant can abrogate the risk of a monogenic disorder."
explanation: >-
The general principle the authors open with, and precisely what makes single-locus
genotype-to-phenotype prediction unsafe here. Graded OTHER because the sentence is
the paper's framing statement rather than a result of any study arm.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A dominant allele in a predicted methyltransferase gene, METTL13, entirely suppresses human deafness associated with a GAB1 variant."
explanation: >-
Suppression is complete rather than partial, so the modifier genotype changes the
predicted outcome categorically.
- name: Exclusion of intrafamilial genetic heterogeneity
description: >-
A large consanguineous pedigree in which some haplotype homozygotes hear normally has two
readings: a modifier, or two different deafness genes segregating in different sibships.
The second was tested directly by exome sequencing six deaf individuals from six sibships
plus a non-penetrant individual, and only the GAB1 allele was shared. Any future family
proposed as DFNB26 should be held to the same test.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "WES data did not reveal any potential pathogenic variants shared among affected individuals, except for the c.347G>A allele in GAB1 at the DFNB26 locus"
explanation: The exome result that excludes the intrafamilial-heterogeneity alternative.
treatments:
- name: Cochlear Implantation
description: >-
Prelingual severe-to-profound sensorineural hearing loss is the standard indication for
cochlear implantation, and that is the management this phenotype attracts. No
DFNB26-specific implant outcome has been reported, and the localisation of GAB1
expression to spiral ganglion neurons rather than hair cells is a reason to ask whether
neural substrate is intact in this genotype rather than to assume it - but no data
address that either way, so nothing here should be read as a genotype-specific
recommendation.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
notes: >-
No evidence item is attached. Neither cited paper mentions cochlear implantation at all
(checked by searching both cached records for "implant"), so there is nothing here to
quote, and no DFNB26-specific implant outcome has been published. The indication stated
in the description is general standard of care for prelingual severe-to-profound
sensorineural hearing loss rather than anything this disease's literature establishes.
target_mechanisms:
- target: Profound Prelingual Sensorineural Hearing Loss
description: Bypasses the sensory deficit; does not act on MET/HGF signalling.
- name: Genetic Counseling
description: >-
Counselling for this family is unusually delicate, because a recessive genotype that
normally carries a high recurrence risk is modified by an unlinked dominant allele.
Recurrence risk depends on the METTL13 genotype as well as the GAB1 one, and a
non-penetrant homozygote is a carrier of a fully penetrant risk for offspring who do not
inherit the suppressor.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:11101839
reference_title: Dominant modifier DFNM1 suppresses recessive deafness DFNB26.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are seven unaffected family members who are also homozygous for the DFNB26-linked haplotype and thus are non-penetrant."
explanation: >-
The non-penetrance that makes recurrence-risk counselling from the GAB1 genotype alone
misleading.
animal_models:
- name: gab1 morpholino knockdown zebrafish with human mRNA rescue
species: Zebrafish
genotype: gab1 translation-blocking and splice-site morpholino knockdown
publication: PMID:29408807
description: >-
A morpholino knockdown used as an in vivo assay for allele function rather than as a
disease model. Two independent morpholinos, plus p53 co-injection, give the same
developmental phenotype. Human GAB1 mRNA rescues; mRNA carrying p.Gly116Glu rescues only
partially, which is the in vivo demonstration that the allele is hypomorphic. Adding
human METTL13 mRNA carrying the suppressor allele significantly attenuates the phenotype,
while wild-type METTL13 mRNA does not.
genes:
- preferred_term: GAB1
term:
id: hgnc:4066
label: GAB1
- preferred_term: METTL13
term:
id: hgnc:24248
label: METTL13
modeled_mechanisms:
- target: GAB1 p.Gly116Glu Hypomorphic PH-Domain Variant
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
Establishes in a whole animal that p.Gly116Glu retains partial function and that the
METTL13 suppressor allele acts on the GAB1 lesion allele-specifically.
limitations: >-
The scored phenotype is early embryonic development - eye formation, budding-stage
arrest, epiboly delay - not hearing, so the model tests allele function rather than
the disease. Morpholino knockdown is transient and not equivalent to the human
homozygous missense state, and the rescue is of a knockdown by exogenous human mRNA
rather than of an engineered mutant fish. No auditory or lateral-line readout was
reported.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "MO resulted in significant rescue at the 10- to 12-somite stage, whereas mRNA encoding the hypomorphic p.Gly116Glu variant resulted in partial rescue."
explanation: >-
Partial rather than absent rescue by the mutant mRNA is the in vivo statement that
the allele is hypomorphic. The quote starts at "MO" because the preceding clause -
coinjection of 1 ng wild-type human GAB1 mRNA with the zebrafish gab1
translation-blocking morpholino - is split across a line break in the cache.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "a second MO directed against the intron 2/exon 3 splice junction of gab1 revealed the same developmental deficits"
explanation: >-
A second independent morpholino gives the same phenotype, which is the control that
makes the knockdown attributable to gab1.
readouts:
- name: Morphant developmental phenotype class at the 10- to 12-somite stage
target: GAB1 p.Gly116Glu Hypomorphic PH-Domain Variant
direction: RESTORED
interpretation: >-
Restored by wild-type human GAB1 mRNA and only partially by p.Gly116Glu mRNA;
separately attenuated by co-injecting suppressor-allele METTL13 mRNA but not
wild-type METTL13 mRNA.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observed a significant rescue when 250 pg human METTL13 mRNA with the modifier variant mRNA was injected along with human GAB1-mutant mRNA"
explanation: >-
The suppressor arm of the rescue experiment. The reduced 250 pg dose was chosen by
the authors because the human modifier allele is heterozygous; the significance
figure that follows in the source is cut here because the word "phenotype" is
split across a hyphenated line break in the PDF-derived cache.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We did not detect rescue when we used WT human METTL13 mRNA (NM_015935) in combination with mutant human GAB1 mRNA"
explanation: >-
The allele-specific control: only the suppressor allele rescues, so the effect is a
property of p.Arg544Gln rather than of METTL13 dosage.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Thus, morphant developmental deficits appear to be specific to the knockdown of gab1 expression."
explanation: >-
The authors' own conclusion that the assay reports on gab1 rather than on morpholino
toxicity, which is what licenses reading the rescue results.
discussions:
- discussion_id: dfnb26_mettl13_suppression_mechanism
kind: KNOWLEDGE_GAP
prompt: >-
Does normalising SPRY2 expression cause the suppression of DFNB26 deafness by METTL13
p.Arg544Gln, or is SPRY2 only a marker of it?
attaches_to:
- pathophysiology#SPRY2 Upregulation
- pathophysiology#Dysregulated MET/HGF Signaling
rationale: >-
The correlative evidence is strong and unusually clean. Thirty-seven MET/HGF pathway
transcripts were measured in lymphoblastoid lines from the same family; fourteen are
dysregulated in deaf and non-penetrant homozygotes alike - thirteen down and PI3K up -
and only SPRY2 tracks hearing status. METTL13 is in a complex with GAB1 and SPROUTY2,
so it is positioned to act there.
But nothing in the reported work shows that changing SPRY2 changes hearing. The
measurement is in lymphoblastoid cells, not cochlea, and the zebrafish rescue scores an
early developmental phenotype, not an auditory one.
The biochemical half of the gap has narrowed since the disease paper was written, and
the question should be posed against what is now known rather than against the 2018
annotation. METTL13 is not an enzyme of unknown activity: it is a dual methyltransferase
for eEF1A, and p.Arg544Gln falls in MT13-C, the domain that trimethylates the eEF1A N
terminus. So the modifier now has a candidate reaction to act through. What is still
entirely open is whether it acts through eEF1A methylation at all - a PubMed sweep of
METTL13 crossed with eEF1A and with deafness returns no report of an eEF1A methylation
measurement in any DFNB26 sample or model, and none of the eEF1A methylation literature
touches hearing - and by what route a change in translation elongation would reach
SPROUTY2 levels specifically. The authors say
"plausible mechanism" of the SPRY2 correlation, and that is still the right strength.
What would settle it is a manipulation rather than a correlation: lower SPRY2 in a
GAB1-hypomorphic cochlear context and ask whether hearing is preserved. No mouse model of
the human GAB1 allele exists to do that in, which is the practical bottleneck - the Gab1
null is embryonic lethal, so a knock-in of p.Gly116Glu is the required reagent. A cheaper
intermediate step is now available too: assay eEF1A N-terminal and Lys55 methylation in
the existing lymphoblastoid lines from this family, which would say whether the
suppressor allele changes METTL13 output at all.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Among the genes examined, only SPRY2 was regulated differently when affected and nonpenetrant individuals"
explanation: >-
SPRY2 is the single transcript that differs between the two clinical groups. Graded
IN_VITRO because the comparison is between lymphoblastoid cell lines. Truncated
before "homozygous for the GAB1 variant were compared", which is split across a
hyphenated line break; the same paper's abstract states that comparison in full and is
quoted for it in the SPRY2 Upregulation node.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
snippet: "METTL13 is predicted to have methyltransferase activity, spermidine/spermine synthase activity, or ubiquinone synthase activity, but these functions of METLL13 have not been experimentally demonstrated"
explanation: >-
The state of knowledge as the disease paper found it, quoted because it is what the
suppressor claim was originally built on. It has since been superseded: PMID:30143613
and PMID:30612740, both later than this paper, demonstrate METTL13 methyltransferase
activity on eEF1A. Retained as the historical baseline, not as a current negative.
- reference: PMID:30143613
reference_title: The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner"
explanation: >-
Supplies the candidate reaction the 2018 statement above says was missing, which is
what makes the remaining question the sharper one this discussion asks: whether the
suppressor acts through eEF1A methylation, and by what route that reaches SPROUTY2.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
snippet: "Additional model systems will be required to understand in greater detail the role of the GAB1-mediated signaling pathway that is essential for normal hearing."
explanation: >-
The authors' own statement that the mechanistic detail requires models they did not
have. Graded OTHER: it is a future-work statement, not data of any study type.
- discussion_id: dfnb26_suppressor_as_therapeutic_strategy
kind: KNOWLEDGE_GAP
prompt: >-
Could a METTL13-based intervention suppress hearing loss caused by other MET/HGF pathway
genes - SPRY2, MET, HGF - and not only the GAB1 allele it was found with?
attaches_to:
- pathophysiology#Dysregulated MET/HGF Signaling
- treatments#
rationale: >-
This is the reason a single-family disease is worth a full entry. A naturally occurring
human allele that completely abolishes a monogenic deafness phenotype is a therapeutic
lead in a way that a disease gene is not, and the pathway it acts on already contains
several established deafness genes: HGF variants cause DFNB39, a MET variant is
associated with DFNB97, and SPRY2 loss causes hearing loss in mice. If the suppressor
acts on the pathway rather than on GAB1 specifically, its reach is much wider than
DFNB26.
The evidence does not yet distinguish those. In the zebrafish assay the suppressor was
only ever tested against the GAB1-mutant background, so pathway-level versus
allele-specific action is untested. The authors state the wider possibility as
speculation, and it is recorded here at that strength. The tractable next step is the
one they imply: run the same rescue assay against knockdowns of spry2, met and hgf.
evidence:
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
snippet: "Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders."
explanation: >-
The therapeutic proposal, stated by the authors as a potential rather than a result.
Graded OTHER because it is a proposal, not an observation from any study arm.
- reference: PMID:29408807
reference_title: Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: "we also speculate that the modifier allele of METTL13 may reduce the severity of sensorineural hearing loss"
explanation: >-
The extension being proposed, in the authors' own hedged wording. Graded OTHER
because the sentence is explicitly labelled speculation. Marked INDIRECT
because it is labelled speculation and rests on the interaction data rather than on any
test in another genotype. The quote is cut before the list of genes it names - SPRY2,
MET and HGF - because "variants" is split across a hyphenated line break in the cache;
those genes are named in this discussion's rationale.
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.
Record notes
Literature base. A PubMed sweep run on 2026-09-04 covered GAB1 crossed with hearing loss and deafness, DFNB26, DFNM1, METTL13, METTL13 crossed with deafness, and METTL13 crossed with eEF1A. The two clinical papers on this disease remain the two cited here - no third family and no independent replication has been published. The sweep did close a real gap on the modifier side: METTL13's enzymatic activity, described as merely predicted in the 2018 JCI paper, was characterised later that same year (PMID:30143613) and independently in 2019 (PMID:30612740), and both are now cited. PMID:39062623 (MAP3K1/DFNB128) surfaces on a GAB1-deafness query but concerns a different locus and is not cited. A falcon deep-research report was also generated and is committed at research/Autosomal_Recessive_Nonsyndromic_Hearing_Loss_26-deep-research-falcon.md. No curation was drawn from it, and its relevance profile says why: the validator scored only 1 of its 5 verified references as on topic. Five of its twelve numbered citations are the same 2018 JCI paper already cited here as PMID:29408807; the remainder are adjacent-locus deafness papers - Mujtaba 2015 on MET/DFNB97, Faridi 2024 on MAP3K1/DFNB128 (which is PMID:39062623, the paper this sweep had already examined and declined), and the Naz and Friedman growth-factor review - plus an Open Targets query. None reports on DFNB26. The manual sweep therefore remains the working literature base for this entry, and the report serves as a retrieval check that surfaced nothing it had missed. Reference cache duplication. references_cache/DOI_10.1172_JCI97350.md and references_cache/DOI_10.1172_jci97350.md are the same article in two DOI casings. Both are present deliberately: the deep-research citation list emits the lowercase form and the fetcher keys on the literal string, so removing either one would make reference validation non-deterministic. This is not a stray duplicate. GeneReviews. PMID:20301607, the Genetic Hearing Loss Overview, is cached and is tagged GeneReviews in four sibling hearing-loss entries (ADNSHL_41, Auditory_Neuropathy, COL11A2_Hearing_Loss and X-linked_Nonsyndromic_Hearing_Loss), but it is deliberately not tagged here. Its cached record is abstract-only - the body is the chapter's six-point statement of scope and nothing more - and contains no occurrence of GAB1, METTL13, DFNB26 or DFNM1, so tagging it would produce a tagged-but-not-mined reference. There is no GAB1-specific GeneReviews chapter. This paragraph records the negative so it is auditable rather than looking like an omission, following the pattern in kb/disorders/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_2B.yaml.
Review round 2: reconcile notes with the committed deep-research artifact · 2026-09-04T17:15:57Z · View source
Addressed the CHANGES_REQUESTED review of 2026-09-04T08:10Z on PR #10904, which found one new blocking item introduced by the previous round's fix. IMPORTANT (fixed). The notes: literature-base paragraph still said no deep-research provider report was generated, which commit 5e3db82 in this same PR falsified by adding research/Autosomal_Recessive_Nonsyndromic_Hearing_Loss_26-deep-research-falcon.md. Rewrote that sentence to name the report and say what was taken from it, which is nothing, with the reason: the validator scored 1 of 5 verified references as on topic. The paragraph now records the composition behind that number - five of the report's twelve numbered citations are the same 2018 JCI paper already cited as PMID:29408807, and the rest are adjacent-locus deafness papers (Mujtaba 2015 MET/DFNB97; Faridi 2024 MAP3K1/DFNB128, verified via NCBI esummary to be PMID:39062623, the paper the manual sweep had already declined; the Naz and Friedman growth-factor review) plus an Open Targets query. None reports on DFNB26. The manual sweep therefore remains the working literature base and the report serves as a retrieval check. The rest of the paragraph was kept intact. The prior round's history record was left untouched; history is append-only. SUGGESTION (taken). Recorded the c.1631G>A / c.1634G>A nomenclature discrepancy in the METTL13 variant description, with the counts checked against the cache: PMID:29408807 prints c.1631G>A eight times (Sanger results, Table 2 against NM_015935, Figure 1E exon 6 legend) and c.1634G>A twice (zebrafish rescue narrative and discussion). The entry uses c.1631G>A, which is the form the sequence-level results carry. SUGGESTION (taken). Recorded in notes why references_cache/DOI_10.1172_JCI97350.md and references_cache/DOI_10.1172_jci97350.md both exist: the deep-research citation list emits the lowercase DOI and the fetcher keys on the literal string, so both are needed for deterministic reference validation. SUGGESTION (declined, with the reasoning recorded in the item's explanation). The reviewer noted the snippet at the hypomorphic-allele item spans an in-vitro lipid-binding assay and a zebrafish rescue in one sentence. It cannot be split: it is a single sentence and no contiguous substring carries the hypomorphic conclusion without the cross-arm attribution. Both arms are already carried separately with their own grades in this entry - the quantified PIP-array result as IN_VITRO in the same node, the zebrafish morphant rescue as MODEL_ORGANISM under the METTL13 modifier - so nothing is lost. The explanation now states that the sentence is a cross-arm synthesis and that it is graded on the biochemical arm. Preserved. The METTL13 suppressor remains relationship_type: MODIFIER rather than digenic, with HP:0010984 left unbound. The MT13-C / MT13-N assignment established in the previous round is unchanged: p.Arg544Gln sits in MT13-C, which targets the eEF1A N terminus, while MT13-N is the Lys55 methyltransferase. Validation. just validate, validate-terms, count-verified-snippets (51/51), check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all pass on the file. Whole-KB check-folded-hyphens, check-title-snippets, check-snippet-length and check-snippet-grading report no new divergences. No cache CSV or references_cache file changed in this round.
Review round 1: address CHANGES_REQUESTED on PR #10904 · 2026-09-04T06:38:07Z · View source
Addressed the four IMPORTANT findings and four suggestions in the automated review of PR #10904. Fixed: - METTL13 enzymatic activity (finding 2). The curator prose asserting that METTL13's predicted activities have never been demonstrated was outdated and is rewritten. PMID:30143613 (Jakobsson et al., Nat Commun 2018) and PMID:30612740 (Liu et al., Cell 2019) were fetched and are now cited on the METTL13 genetic entry and in the knowledge-gap discussion. The 2018 JCI snippet is unchanged and is retained as the historical baseline, with an explanation saying it has been superseded. - The review's domain assignment is wrong in one detail and the entry does not repeat it. The review states p.Arg544Gln falls in 'MTase13-C, the eEF1A-Lys55 methyltransferase domain'. Jakobsson assigns the Lys55 activity to MT13-N and the eEF1A N-terminal activity to MT13-C, and Liu independently shows residues 1-401 suffice for Lys55 methylation while the C-terminal domain is dispensable for it. Arg544 sits in MT13-C (crystallised core residues 470-699), so the candidate activity for the suppressor is eEF1A N-terminal methylation, not Lys55 methylation. - evidence_source consistency (finding 3). Three items quoting the lymphoblastoid RT-PCR panel were regraded HUMAN_CLINICAL -> IN_VITRO; four items quoting authorial framing, future work, a therapeutic proposal and explicit speculation were regraded HUMAN_CLINICAL -> OTHER. Each explanation now says why. - references block and GeneReviews decision (finding 4). Added a references: block for the four cited papers and a top-level notes paragraph recording that PMID:20301607 is not tagged, because its cached record is abstract-only and contains no GAB1/METTL13/DFNB26/DFNM1 content. - Fourteen-vs-thirteen count (suggestion 5). The discussion rationale said thirteen; the source lists thirteen downregulated plus PI3K upregulated. Corrected to fourteen with the breakdown. - Mouse provenance (suggestion 8). The spiral-ganglion node description now says the LacZ reporter and colocalisation data are mouse. - Cochlear implantation (suggestion 7). Neither cached paper mentions implantation (verified by searching both records), so no evidence item was manufactured; a notes field records the search and the absence. - Prelingual Onset (suggestion 6). Kept as its own phenotype and the disconnection made explicit in notes: it is the timing axis of the same clinical event rather than a separate consequence, so no source supports an edge; folding it into an onset: block would require choosing an OnsetEnum value, and both sources say only 'prelingual', which does not distinguish congenital from neonatal or infantile. Declined: - No deep-research artifact was added (finding 1). CLAUDE.md forbids hand-writing markdown into research/, and no provider recipe was available. A manual PubMed sweep was run instead (GAB1 x hearing loss/deafness, DFNB26, DFNM1, METTL13, METTL13 x deafness, METTL13 x eEF1A) and is recorded in the entry's top-level notes. It confirmed no third family and no independent replication of the disease association, and it surfaced the two METTL13 papers that finding 2 turns on. The METTL13 MODIFIER-not-digenic modelling and the unbound HP:0010984 are unchanged; the review endorsed both. Validation: just validate (51/51 snippets verified), validate-terms, validate-disorders, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-title-snippets, check-snippet-length, check-snippet-grading all pass.
DFNB26 is an exceptionally rare Mendelian form of prelingual, bilateral, severe-to-profound sensorineural hearing loss. Current evidence is centered on one large consanguineous Pakistani pedigree, PK-2. The disease allele is homozygous GAB1 c.347G>A, p.(Gly116Glu), a hypomorphic missense substitution in the pleckstrin-homology domain. A second locus, DFNM1, contains a dominant METTL13 c.1631G>A, p.(Arg544Gln) modifier that can suppress deafness in individuals homozygous for the GAB1 allele. Consequently, penetrance cannot be interpreted from GAB1 genotype alone in this family. Functional support comes from biochemical and cell assays, patient lymphoblastoid cells, zebrafish perturbation/rescue, mouse inner-ear localization, and more recent mouse cochlear single-cell data—not from a disease-specific mammalian knock-in model. (yousaf2018modifiervariantof pages 1-3, yousaf2018modifiervariantof pages 8-10, yousaf2018modifiervariantof pages 7-8, yousaf2018modifiervariantof pages 3-4)
| Evidence domain | DFNB26 finding | Evidence status | Source |
|---|---|---|---|
| Disease/locus | Autosomal recessive nonsyndromic hearing loss 26 (DFNB26), originally linked in Pakistani family PK-2 to a 1.5-cM interval at chromosome 4q31 | Demonstrated by human linkage and segregation | (yousaf2018modifiervariantof pages 1-3, yousaf2018modifiervariantof pages 3-4) |
| Causal variant | Homozygous GAB1 transcript NM_207123 c.347G>A, p.(Gly116Glu); affects a conserved residue in the pleckstrin-homology domain and was absent from the examined controls and 1000 Genomes, NHLBI-ESP, and ExAC | Demonstrated in one extended pedigree; functional evidence supports a hypomorphic allele | (yousaf2018modifiervariantof pages 7-8, yousaf2018modifiervariantof pages 3-4) |
| Phenotype | Prelingual, bilateral, severe-to-profound/profound sensorineural hearing loss without reported extra-auditory manifestations | Demonstrated clinically in PK-2; exact thresholds, ages, progression, and individual-level audiograms were not reported in the extracted evidence | (yousaf2018modifiervariantof pages 7-8, naz2020growthfactorand pages 21-23) |
| Genetic modifier | A dominant modifier at DFNM1, METTL13 c.1631G>A, p.(Arg544Gln), was carried by normal-hearing individuals homozygous for GAB1 p.Gly116Glu; affected homozygotes lacked the modifier | Demonstrated by pedigree segregation; suppression supported experimentally. One extracted passage reports c.1634G>A, but the primary-study sequence-level result is c.1631G>A, so transcript-version verification is advisable | (yousaf2018modifiervariantof pages 1-3, yousaf2018modifiervariantof pages 7-8, yousaf2018modifiervariantof pages 3-4) |
| Molecular mechanism | GAB1 functions as an adaptor in HGF–MET signaling. p.Gly116Glu impairs PH-domain lipid-related function; affected lymphoblastoid cells showed selective SPRY2 upregulation, and GAB1, METTL13, and SPRY2 formed a supported tripartite complex | GAB1 dysfunction and signaling dysregulation are experimentally supported; the complete cochlear chain from variant to hair-cell dysfunction is inferred rather than demonstrated | (yousaf2018modifiervariantof pages 8-10, yousaf2018modifiervariantof pages 6-7, mujtaba2015amutationof pages 4-6) |
| Evidence systems | Human linkage, exome sequencing, segregation, and lymphoblastoid-cell expression; biochemical lipid-binding and co-immunoprecipitation assays; COS-7 interaction assays; zebrafish morpholino/mRNA rescue; mouse inner-ear expression and colocalization; later mouse cochlear single-cell transcriptomic context | Mixed human, in vitro, zebrafish, mouse-localization, and transcriptomic evidence; no reported mammalian GAB1 p.Gly116Glu knock-in model | (yousaf2018modifiervariantof pages 1-3, yousaf2018modifiervariantof pages 8-10, yousaf2018modifiervariantof pages 6-7, faridi2024deafnessdfnb128associated pages 8-10) |
| Major data gaps | No replicated unrelated DFNB26 families, disease-specific prevalence/incidence, quantitative penetrance, carrier frequency, longitudinal natural history, validated prognostic biomarkers, DFNB26-specific therapy/trial, or definitive disease-specific mammalian model identified | Unavailable; mechanism, penetrance, and genotype–phenotype estimates remain constrained by a single pedigree | (yousaf2018modifiervariantof pages 1-3, yousaf2018modifiervariantof pages 7-8, naz2020growthfactorand pages 21-23) |
Table: Compact summary of the human genetic, modifier, mechanistic, and model-system evidence for GAB1-related DFNB26. It distinguishes demonstrated findings from pathway-level inference and highlights the major knowledge gaps.
Evidence caveat. No replicated unrelated DFNB26 families, disease-specific prevalence estimate, prospective natural-history cohort, or targeted clinical trial was identified. Many requested database fields therefore remain unknown rather than negative.
DFNB26 is an autosomal-recessive, nonsyndromic auditory disorder caused by biallelic pathogenic variation in GAB1, encoding GRB2-associated binding protein 1. The reported phenotype is prelingual, bilateral, severe-to-profound or profound sensorineural deafness without recognized extra-auditory manifestations. An authoritative growth-factor review describes GAB1 as a mediator of HGF and IGF1 signaling and lists the DFNB26 phenotype as “prelingual, bilateral, sensorineural, and profound.” (yousaf2018modifiervariantof pages 7-8, naz2020growthfactorand pages 21-23)
The evidence is principally family-level research data, not EHR-derived surveillance or an aggregated population registry. Whole-exome sequencing included six deaf relatives from six sibships, one normal-hearing nonpenetrant relative, and an unrelated normal control. (yousaf2018modifiervariantof pages 3-4)
The only reported disease allele is germline homozygous GAB1 NM_207123:c.347G>A, p.(Gly116Glu). It affects a conserved residue in the GAB1 pleckstrin-homology domain and was absent from the examined Pakistani/Indian controls and from 1000 Genomes, NHLBI-ESP, and ExAC. Eight computational predictors called it damaging, while lipid-binding and zebrafish experiments supported a partial-loss-of-function, or hypomorphic, effect. (yousaf2018modifiervariantof pages 7-8, yousaf2018modifiervariantof pages 3-4)
No other validated susceptibility, protective, or modifier alleles are known specifically for DFNB26. There is no evidence for anticipation.
No noise, infection, drug, diet, smoking, alcohol, occupational exposure, or other environmental factor has been shown to cause or modify DFNB26. General ototoxic exposures may add acquired injury to genetically impaired hearing, but this is clinical precaution rather than a demonstrated DFNB26 gene–environment interaction. No infectious etiology applies.
| Phenotype | Characteristics in DFNB26 | Suggested HPO term |
|---|---|---|
| Sensorineural hearing impairment | Primary clinical sign; bilateral | HP:0000407, sensorineural hearing impairment; HP:0008619, bilateral sensorineural hearing impairment |
| Severe-to-profound/profound hearing loss | Reported in affected PK-2 relatives; exact individual thresholds were unavailable in the extracted report | HP:0012715, severe hearing impairment; HP:0012714, profound hearing impairment |
| Prelingual onset | Present before speech acquisition; exact neonatal versus infant age was not reported | HP:0000399, prelingual sensorineural hearing impairment; consider HP:0003577, congenital onset only if confirmed for an individual |
| Nonsyndromic presentation | No extra-auditory manifestations reported | Encode absence cautiously; do not infer normality for every organ from incomplete examinations |
| Speech/language consequences | Expected with untreated prelingual profound loss, but not quantified in PK-2 | HP:0000750, delayed speech and language development, only when documented |
The hearing phenotype is described as severe-to-profound in the primary investigation and as profound in later summaries. Frequencies cannot be estimated beyond saying that hearing loss tracked GAB1 homozygosity in relatives lacking the suppressor. Exact audiograms, vestibular measurements, longitudinal progression, tinnitus, and quantitative speech outcomes were not available. (yousaf2018modifiervariantof pages 7-8, naz2020growthfactorand pages 21-23)
Quality of life. Disease-specific EQ-5D, SF-36, PROMIS, or hearing-related quality-of-life measurements have not been reported. Untreated prelingual profound hearing loss can materially affect spoken-language acquisition, education, communication, and social participation, but those generic consequences should not be stored as observed PK-2 outcomes.
DFNB26 is genetically initiated. No toxin, radiation, pollution, occupation, lifestyle behavior, or pathogen has been causally associated with it. Standard hearing-conservation measures—avoiding excessive noise and unnecessary ototoxic medication, vaccination against preventable infections that can damage hearing, and prompt treatment of otitis—may preserve residual auditory function but do not prevent inheritance or reverse GAB1 dysfunction.
Activated MET recruits GAB1/GRB2 and can engage PI3K, PTPN11/SHP2, PTK2, STAT, and RAS–RAF–MAPK/ERK signaling. These pathways regulate proliferation, survival, migration, morphogenesis, and tissue maintenance. Related HGF, MET, GAB1, and MAP3K1 deafness genes reinforce a shared auditory signaling network, but it is not established that every branch is abnormal in DFNB26 cochleae. (faridi2024deafnessdfnb128associated pages 1-2, mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 5-7)
Suggested terms include GO:0007169 transmembrane receptor protein tyrosine kinase signaling; GO:0008286 insulin receptor signaling pathway, where appropriate for GAB1; GO:0048011 neurotrophin TRK receptor signaling; GO:0043066 negative regulation of apoptotic process; GO:0007165 signal transduction; GO:0048870 cell motility; and GO:0007420 brain development. Exact GAB1 annotations should be drawn from the current GO release rather than inferred wholesale from the pathway.
Mouse immunolocalization found overlapping Gab1/Mettl13 expression in spiral ganglion neurons, cochlear sensory-neuron fibers, supporting cells, and vestibular/cochlear regions. A 2024 mouse cochlear single-cell/single-nucleus analysis provided newer pathway context: Gab1, Hgf, and Map3k1 were detected in stria-vascularis marginal cells; Met in intermediate cells; pathway components also occurred in spiral ganglion neurons, with little expression in inner or outer hair cells in those datasets. This argues against assuming that DFNB26 is a hair-cell-autonomous disorder. (yousaf2018modifiervariantof pages 6-7, faridi2024deafnessdfnb128associated pages 8-10)
Suggested CL terms: CL:0000210 photoreceptor-like sensory receptor cell is not recommended because it is too broad; use current ontology terms for spiral ganglion neuron, inner-ear supporting cell, stria vascularis marginal cell, and stria vascularis intermediate cell after ontology-browser verification. Suggested processes include neuronal signaling, epithelial morphogenesis, survival, and cochlear ion-homeostasis support.
Onset is prelingual and likely congenital or very early childhood, but a precise birth-to-diagnosis interval was not reported. The available family data do not establish whether thresholds are stable or progressive. The condition should therefore be represented as chronic/lifelong severe auditory impairment, with progression coded unknown, not stable. There are no defined stages, spontaneous remissions, or episodic attacks.
The critical clinical period is early infancy and childhood, when auditory access is required for spoken-language development. Newborn detection, prompt etiologic testing, amplification, communication support, and timely cochlear-implant evaluation are therefore important even though no DFNB26-specific timing trial exists.
No blood chemistry, metabolite, protein biomarker, biopsy, or characteristic imaging sign diagnoses DFNB26. CT/MRI is used for cochlear-implant planning or suspected structural abnormalities, not molecular confirmation.
The differential includes other congenital/prelingual AR nonsyndromic hearing losses, auditory neuropathy such as OTOF-related disease, enlarged-vestibular-aqueduct/SLC26A4 disease, congenital CMV, ototoxic exposure, and syndromic disorders whose non-auditory findings emerge later. DFNB26 is distinguished by biallelic pathogenic GAB1 variants with compatible segregation and, where relevant, METTL13 modifier status.
DFNB26 is not known to shorten life expectancy or cause disease-specific mortality. The principal morbidity is lifelong auditory disability and its communication, educational, and psychosocial consequences. Untreated sensory-neural function is not expected to recover spontaneously. Hearing technology can improve auditory access but does not restore normal GAB1 signaling.
No DFNB26-specific survival statistics, disability-adjusted life years, cochlear-implant speech scores, validated prognostic biomarkers, or recovery rates are available. Important practical prognostic variables are age at identification/intervention, hearing level, residual hearing, consistent device use, communication access, educational support, and implant candidacy—not the GAB1 genotype alone. METTL13 status is a biologically compelling penetrance marker but has been demonstrated in only one pedigree.
There is no approved GAB1- or METTL13-directed pharmacotherapy, no established pharmacogenomic rule, and no DFNB26-specific gene, RNA, cell, or immune therapy. The clinical-trial search found no relevant interventional DFNB26 trial.
Current care follows pediatric severe-to-profound hearing-loss practice:
Suggested NCIT concepts include Hearing Aid Device, Cochlear Implantation, Speech and Language Therapy, Audiologic Rehabilitation, and Genetic Counseling; exact NCIT identifiers should be resolved in the current NCI Thesaurus release.
Experimental HGF delivery has ameliorated chemically induced hearing impairment in rats, and HGF–MET signaling is an attractive pathway, but this neither demonstrates efficacy in DFNB26 nor justifies off-label pathway stimulation. MET signaling is pleiotropic and oncologically important, so nonspecific manipulation could carry substantial risk. (mujtaba2015amutationof pages 6-8, mujtaba2015amutationof pages 4-6)
No naturally occurring veterinary disorder attributable to an orthologous GAB1 DFNB26 allele was identified. Relevant orthologs include mouse Gab1 (Mus musculus, NCBI Taxon 10090) and zebrafish gab1 (Danio rerio, NCBI Taxon 7955). These systems support evolutionary conservation of developmental and receptor-signaling functions. There is no zoonotic or cross-species transmission because DFNB26 is inherited, not infectious.
Gab1 morpholino perturbation produced developmental phenotypes, and human GAB1/METTL13 mRNA experiments supported the hypomorphic disease allele and suppressor relationship. Coinjection experiments used 1,000 pg GAB1 and 250 pg METTL13 mRNA; suppressor METTL13 partially rescued the GAB1-associated phenotype. This is the strongest whole-organism functional evidence, but a morpholino developmental phenotype is not identical to human isolated deafness, and zebrafish lateral-line/inner-ear biology cannot establish human cochlear penetrance quantitatively. (yousaf2018modifiervariantof pages 8-10, yousaf2018modifiervariantof pages 3-4)
Mouse evidence is primarily expression/localization: Gab1 and Mettl13 overlap in spiral ganglion neurons, auditory nerve fibers, supporting cells, and other inner-ear structures. Later single-cell datasets place HGF–MET–GAB1-related components prominently in strial and neuronal populations. No reported Gab1 p.Gly116Glu knock-in mouse directly reproduces DFNB26. (yousaf2018modifiervariantof pages 6-7, faridi2024deafnessdfnb128associated pages 8-10)
Patient lymphoblastoid cells enabled pathway-expression comparisons; COS-7 cells, NanoSPD, co-immunoprecipitation, and filopodial-tip assays supported GAB1–METTL13–SPRY2 interaction; lipid-binding assays supported PH-domain dysfunction. Limitations include non-cochlear cell context and uncertain correspondence between expression changes and auditory-cell physiology. (yousaf2018modifiervariantof pages 8-10, yousaf2018modifiervariantof pages 6-7)
The principal disease-defining study remains Yousaf et al., March 2018, Journal of Clinical Investigation, “Modifier variant of METTL13 suppresses human GAB1-associated profound deafness,” DOI: 10.1172/JCI97350. Its central finding was that a dominant METTL13 allele can suppress a recessive GAB1-associated phenotype, making DFNB26 a particularly clear human example of modified Mendelian penetrance. (yousaf2018modifiervariantof pages 1-3)
Recent 2024 work has refined context rather than changed the causal assignment. Faridi et al., published 27 June 2024, placed GAB1/DFNB26 in a broader HGF–MET–GAB1–MAP3K1 deafness network and used mouse cochlear single-cell data to emphasize strial and spiral-ganglion expression rather than a simple hair-cell-only mechanism: DOI 10.3390/genes15070845. (faridi2024deafnessdfnb128associated pages 1-2, faridi2024deafnessdfnb128associated pages 8-10) A 2024 review of Pakistani AR nonsyndromic hearing loss underscores how consanguineous pedigrees have enabled rare-gene discovery while showing that most individually uncommon genes each explain under 2% of cases; this supports describing DFNB26 as ultra-rare rather than assigning an unsupported prevalence. (faridi2024deafnessdfnb128associated pages 1-2)
References
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(yousaf2018modifiervariantof pages 8-10): Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, and Saima Riazuddin. Modifier variant of mettl13 suppresses human gab1–associated profound deafness. Mar 2018. URL: https://doi.org/10.1172/jci97350, doi:10.1172/jci97350. This article has 58 citations and is from a highest quality peer-reviewed journal.
(yousaf2018modifiervariantof pages 7-8): Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, and Saima Riazuddin. Modifier variant of mettl13 suppresses human gab1–associated profound deafness. Mar 2018. URL: https://doi.org/10.1172/jci97350, doi:10.1172/jci97350. This article has 58 citations and is from a highest quality peer-reviewed journal.
(yousaf2018modifiervariantof pages 3-4): Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, and Saima Riazuddin. Modifier variant of mettl13 suppresses human gab1–associated profound deafness. Mar 2018. URL: https://doi.org/10.1172/jci97350, doi:10.1172/jci97350. This article has 58 citations and is from a highest quality peer-reviewed journal.
(naz2020growthfactorand pages 21-23): Sadaf Naz and Thomas B. Friedman. Growth factor and receptor malfunctions associated with human genetic deafness. Clinical Genetics, 97:138-155, Oct 2020. URL: https://doi.org/10.1111/cge.13641, doi:10.1111/cge.13641. This article has 17 citations and is from a peer-reviewed journal.
(yousaf2018modifiervariantof pages 6-7): Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, and Saima Riazuddin. Modifier variant of mettl13 suppresses human gab1–associated profound deafness. Mar 2018. URL: https://doi.org/10.1172/jci97350, doi:10.1172/jci97350. This article has 58 citations and is from a highest quality peer-reviewed journal.
(mujtaba2015amutationof pages 4-6): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.
(faridi2024deafnessdfnb128associated pages 8-10): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.
(OpenTargets Search: autosomal recessive nonsyndromic hearing loss 26): Open Targets Query (autosomal recessive nonsyndromic hearing loss 26, 37 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(faridi2024deafnessdfnb128associated pages 1-2): Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert Morell, Elizabeth Wilson, Ying Xia, Tanveer Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin, and Thomas Friedman. Deafness dfnb128 associated with a recessive variant of human map3k1 recapitulates hearing loss of map3k1-deficient mice. Genes, 15:845, Jun 2024. URL: https://doi.org/10.3390/genes15070845, doi:10.3390/genes15070845. This article has 3 citations.
(naz2020growthfactorand pages 5-7): Sadaf Naz and Thomas B. Friedman. Growth factor and receptor malfunctions associated with human genetic deafness. Clinical Genetics, 97:138-155, Oct 2020. URL: https://doi.org/10.1111/cge.13641, doi:10.1111/cge.13641. This article has 17 citations and is from a peer-reviewed journal.
(mujtaba2015amutationof pages 6-8): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 5 |
| Resolved | 5 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 5 |
| On topic | 1 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 20 |
| Resolved | 20 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 0 |
Every term resolved, and every label the report gave matched.