GJB6

Summary

GJB6 (gap junction protein beta 6, HGNC:4288) is a protein-coding gene on chromosome 13q12.11, encoding Gap junction beta-6 protein (O95452). One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia.

Source: NCBI Gene 10804 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Clouston syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 237 total — 9 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 108
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001110219

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4288
Approved symbol	GJB6
Name	gap junction protein beta 6
Location	13q12.11
Locus type	gene with protein product
Status	Approved
Aliases	EDH, HED, CX30
Ensembl gene	ENSG00000121742
Ensembl biotype	protein_coding
OMIM	604418
Entrez	10804

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 20 protein_coding

ENST00000241124, ENST00000400065, ENST00000400066, ENST00000636852, ENST00000642251, ENST00000643121, ENST00000643211, ENST00000644236, ENST00000644283, ENST00000644667, ENST00000645654, ENST00000646108, ENST00000647029, ENST00000647243, ENST00000909786, ENST00000909787, ENST00000967105, ENST00000967106, ENST00000967107, ENST00000967108

RefSeq mRNA: 7 — MANE Select: NM_001110219 NM_001110219, NM_001110220, NM_001110221, NM_001370090, NM_001370091, NM_001370092, NM_006783

CCDS: CCDS9291

Canonical transcript exons

ENST00000647029 — 5 exons

Exon	Start	End
ENSE00001295958	20229580	20229749
ENSE00001399364	20230698	20230807
ENSE00001401776	20231382	20231505
ENSE00003814336	20221962	20223495
ENSE00003830083	20232194	20232319

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 99.10.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6037 / max 1319.4974, expressed in 252 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136343	4.2260	239
136338	0.7222	84
136339	0.3147	70
136341	0.2225	114
136342	0.0713	27
136340	0.0470	12

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.10	gold quality
gingiva	UBERON:0001828	99.05	gold quality
gingival epithelium	UBERON:0001949	98.93	gold quality
lower esophagus mucosa	UBERON:0035834	98.69	gold quality
penis	UBERON:0000989	98.14	gold quality
mammalian vulva	UBERON:0000997	97.90	gold quality
esophagus mucosa	UBERON:0002469	97.41	gold quality
pharyngeal mucosa	UBERON:0000355	97.02	gold quality
oral cavity	UBERON:0000167	96.89	gold quality
upper leg skin	UBERON:0004262	96.53	gold quality
esophagus squamous epithelium	UBERON:0006920	96.47	gold quality
body of tongue	UBERON:0011876	96.45	gold quality
skin of hip	UBERON:0001554	94.93	gold quality
lateral globus pallidus	UBERON:0002476	94.15	gold quality
nucleus accumbens	UBERON:0001882	94.13	gold quality
medial globus pallidus	UBERON:0002477	93.64	gold quality
globus pallidus	UBERON:0001875	93.38	gold quality
putamen	UBERON:0001874	93.28	gold quality
caudate nucleus	UBERON:0001873	92.97	gold quality
zone of skin	UBERON:0000014	92.74	gold quality
skin of leg	UBERON:0001511	92.51	gold quality
skin of abdomen	UBERON:0001416	92.46	gold quality
amygdala	UBERON:0001876	92.27	gold quality
right frontal lobe	UBERON:0002810	92.13	gold quality
trigeminal ganglion	UBERON:0001675	90.72	gold quality
temporal lobe	UBERON:0001871	90.71	gold quality
anterior cingulate cortex	UBERON:0009835	90.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.09	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.75	gold quality
superior frontal gyrus	UBERON:0002661	89.16	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	13.65
E-ANND-3	yes	9.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX9

miRNA regulators (miRDB)

46 targeting GJB6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-3191-3P	99.45	63.94	356

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• founder deletion mutation in GJB6 cooperating with a GJB2 mutation in Ashkenazi Jews with non-syndromic deafness (PMID:11668644)
• A 342-kb deletion in GJB6 is a cause prelingual deafness. (PMID:11807148)
• A novel connexin 30 mutation in Clouston syndrome. we report a novel mutation V37E within the first transmembrane domain of connexin 30 in a spontaneous case of Clouston syndrome. (PMID:11874494)
• homozygous deletion of a region encompassing this gene causes non syndromic hearing loss (PMID:11896458)
• skin disease-associated Cx30 mutations:impaired trafficking of the protein to the plasma membrane prevented functional CX30 gap junction formation; deafness-associated mutation: protein trafficked to membrane but channel activity was defective (PMID:12419304)
• Permeability and gating properties of connexin 30. (PMID:12767933)
• A G11R missense mutation in the Cx30 gene can cause HED in Chinese Han population . (PMID:12788524)
• GJB2 and GJB6 may have a causative role in deafness (PMID:12865758)
• The large GJB6 deletion was not found in the Austrian non-syndromic hearing loss patients. (PMID:12872268)
• It showed that patients who are compound heterozygous for a 342-kb deletion involving a large portion of the 5’-part of GJB6, encoding connexin 30, and a GJB2 mutation develop NSHL due to a trait with a digenic pattern of inheritance. (PMID:14759569)
• induction of Cx26 and Cx30 near the wound margins in spontaneous wound healing and-even earlier-after the transplantation of keratinocytes. (PMID:15140236)
• We report the first study of GJB2 and GJB6 mutations in Danish patients with NSHI (PMID:15345117)
• Data exclude a digenetic association of del(GJB6-D13S1830) with heterozygous GJB2 mutations as a cause of deafness in a representative sample of the population from Eastern Austria. (PMID:15464308)
• Double heterozygosity with mutations in the GJB6 gene is associated with congenital deafness (PMID:15638823)
• We hereby describe the hearing impairment in Dutch patients with biallelic connexin 26 (GJB2) and GJB2+connexin 30 (GJB6) mutations (PMID:15656949)
• This study mapped a basal GJB6 promoter sequence active in a human keratinocyte cell line. (PMID:15792634)
• mutations in the GJB2 gene and the delGJB6-D13S1830 are prevalent in the Argentinean population in sensorineural deafness (PMID:15964725)
• This is the first evidence of a deafness-associated regulatory mutation of GJB2 and of potential coregulation of GJB2 and GJB6 (PMID:16773579)
• GJB2 mutations, GJB6 deletions, and mtDNA mutations may not be significant in African American and Caribbean Hispanic individuals with hearing impairment (PMID:17357124)
• frequency of 35delG was about 18.5%, however, del(GJB6-D13S1830) was not found in the studied patients with autosomal recessive non-syndromic hearing loss; results support founder effect regarding these mutations (PMID:17368814)
• None of the study children had the 342-kb deletion (delGJB6-D13S1830) in GJB6, which suggests that this mutation does not play a role in hereditary deafness in the African American population (PMID:17426645)
• Mutation of GJB6 gene is infrequent in the Chinese non-syndromic hearing-loss population. (PMID:17438853)
• Cx26 and Cx30 form functional heteromeric and heterotypic channels whose biophysical properties and permeabilities are different from their homotypic counterparts (PMID:17615163)
• findings suggest that loci other than GJB2 and GJB6 contribute to the pathogenesis of autosomal recessive-nonsyndromic sensorineural hearing loss and that the full spectrum of GJB2 sequence changes is not yet fully elucidated (PMID:17666888)
• Cx30 expression in head and neck cancer was drastically reduced compared to apparently normal mucosa while Cx26 expression was almost the same. (PMID:17695503)
• Mutations in connexin 26 and 30 genes are rare in patients with CRS or RARS and do not seem to play a contributory role in the pathogensis of these disorders. (PMID:17989577)
• The frequency for the del(GJB6-D13S1830) was 2.5% in Venezuelan patients with autosomal recessive nonsyndromic hearing loss. (PMID:18294049)
• Some GJB2, GJB3, and GJB6 mutations occurred in deaf students. (PMID:18338563)
• We sequenced the GJB2 and GJB6 genes to examine the role of mutations in these genes.No mutations were found in GJB6 gene. (PMID:18585793)
• The intent of this study was to investigate the prevalence of the point and digenic mutations including large deletions and duplications in the Cx26, 30, and 31 genes in a Swiss patient cohort with autosomal recessive nonsyndromic hearing impairment. (PMID:18607988)
• no apparent differences in speech performance after cochlear implantation between patients with biallelic GJB2 and/or GJB6 mutations and those with deafness of unknown aetiology (PMID:19051073)
• Mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil. (PMID:19125024)
• Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort. (PMID:19173109)
• The results suggest that the cytoskeleton, and especially actin filaments, are important components in the processes of assembly, trafficking and stabilization of Cx30 gap junctions. (PMID:19285977)
• eccrine syringofibroadenoma found in a patient with genetically confirmed GJB6 Clouston syndrome (PMID:19318801)
• Analysis of the GJB6 gene in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss are reported. (PMID:19371219)
• data shows low incidence of pathogenic GJB2 mutations and absence of DeltaGJB6-D13S1830 and A1555G, A3243G and A7445G mitochondrial mutations in North Indian population with non-syndromic hearing impairment. (PMID:19465004)
• The GJB6 del(GJB6-D13S1830) does not cause hearing loss through a digenic mechanism of inheritance, but by eliminating a putative cis-regulatory element located within the deleted region that affects GJB2 expression. (PMID:19723508)
• this study provides unequivocal support for the hypothesis that del(GJB6-D13S1830) eliminates a putative cis-regulatory element located within the deleted region. (PMID:19723508)
• The Vertical epidermal expression patterns of Cx30 significantly correlated with the proliferative index in the epidermal tumor microenvironment but not with the proliferative index in the tumor. (PMID:19844737)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gjb8	ENSDARG00000042707
mus_musculus	Gjb6	ENSMUSG00000040055
rattus_norvegicus	Gjb6	ENSRNOG00000022116

Paralogs (20): GJA8 (ENSG00000121634), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), GJC3 (ENSG00000176402), GJD4 (ENSG00000177291), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB3 (ENSG00000188910), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction beta-6 protein — O95452 (reviewed: O95452)

Alternative names: Connexin-30

All UniProt accessions (6): A0A024RDS4, A0A2R8Y4J9, A0A2R8Y5T6, A0A2R8Y6N2, A0A2R8YCY0, O95452

UniProt curated annotations — full annotation on UniProt →

Function. One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Subunit / interactions. A connexon is composed of a hexamer of connexins. Interacts with CNST.

Subcellular location. Cell membrane. Cell junction. Gap junction.

Disease relevance. Ectodermal dysplasia 2, Clouston type (ECTD2) [MIM:129500] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD2 is an autosomal dominant condition characterized by atrichosis, nail hypoplasia and deformities, hyperpigmentation of the skin, normal teeth, normal sweat and sebaceous gland function. Palmoplantar hyperkeratosis is a frequent feature. Hearing impairment has been detected in few cases. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 1B (DFNB1B) [MIM:612645] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. Deafness, autosomal dominant, 3B (DFNA3B) [MIM:612643] A form of non-syndromic sensorineural hearing loss characterized by a variable phenotype, ranging from bilateral middle to high frequency hearing loss to profound sensorineural deafness. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the connexin family. Beta-type (group I) subfamily.

RefSeq proteins (7): NP_001103689, NP_001103690, NP_001103691, NP_001357019, NP_001357020, NP_001357021, NP_006774 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029

UniProt features (20 total): sequence variant 8, topological domain 5, transmembrane region 4, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95452-F1	82.33	0.48

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 356 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, REACTOME_MEMBRANE_TRAFFICKING, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, GOBP_CARDIAC_CONDUCTION_SYSTEM_DEVELOPMENT, MARTINEZ_RB1_TARGETS_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_EAR_DEVELOPMENT, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_CELL_COMMUNICATION_BY_ELECTRICAL_COUPLING, GOBP_EAR_MORPHOGENESIS

GO Biological Process (15): sinoatrial node development (GO:0003163), cell-cell signaling (GO:0007267), sensory perception of sound (GO:0007605), negative regulation of cell population proliferation (GO:0008285), gap junction assembly (GO:0016264), response to lipopolysaccharide (GO:0032496), maintenance of blood-brain barrier (GO:0035633), ear morphogenesis (GO:0042471), inner ear development (GO:0048839), response to electrical stimulus (GO:0051602), transmembrane transport (GO:0055085), cellular response to glucose stimulus (GO:0071333), gap junction-mediated intercellular transport (GO:1990349), cell communication (GO:0007154), cell communication by electrical coupling (GO:0010644)

GO Molecular Function (6): gap junction channel activity (GO:0005243), microtubule binding (GO:0008017), beta-tubulin binding (GO:0048487), actin filament binding (GO:0051015), gap junction channel activity involved in cell communication by electrical coupling (GO:1903763), protein binding (GO:0005515)

GO Cellular Component (8): actin filament (GO:0005884), gap junction (GO:0005921), connexin complex (GO:0005922), apical plasma membrane (GO:0016324), cell junction (GO:0030054), plasma membrane (GO:0005886), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gap junction trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
ear development	2
cellular process	2
tubulin binding	2
cellular anatomical structure	2
cardiac conduction system development	1
atrial cardiac muscle tissue development	1
signaling	1
sensory perception of mechanical stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell-cell junction assembly	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
tissue homeostasis	1
embryonic organ morphogenesis	1
sensory organ morphogenesis	1
anatomical structure development	1
response to abiotic stimulus	1
transport	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
intercellular transport	1
wide pore channel activity	1
actin binding	1
protein-containing complex binding	1
gap junction channel activity	1
cell communication by electrical coupling	1
binding	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
cell-cell junction	1
gap junction	1
plasma membrane protein complex	1
apical part of cell	1
plasma membrane region	1
membrane	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJB6	GJB2	P29033	981
GJB6	GJA1	P17302	971
GJB6	GJB1	P08034	897
GJB6	GJC1	P36383	895
GJB6	MYO15A	Q9UKN7	866
GJB6	MYO7A	P78427	778
GJB6	CNST	Q6PJW8	739
GJB6	SLC26A4	O43511	719
GJB6	CDH23	Q9H251	714
GJB6	WFS1	O76024	694
GJB6	GJC2	Q5T442	653
GJB6	KCNJ10	P78508	645
GJB6	GJB3	O75712	636
GJB6	PANX1	Q96RD7	610
GJB6	TJP2	Q9UDY2	609

IntAct

35 interactions, top by confidence:

A	B	Type	Score
GJB6	KLRC1	psi-mi:“MI:0915”(physical association)	0.560
GJB6	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	GJB6	psi-mi:“MI:0915”(physical association)	0.560
GJB6	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
GJB6	MS4A13	psi-mi:“MI:0915”(physical association)	0.560
GJB6	EBP	psi-mi:“MI:0915”(physical association)	0.560
SEC22B	GJB6	psi-mi:“MI:0915”(physical association)	0.560
GJB6	GPR61	psi-mi:“MI:0915”(physical association)	0.560
GJB6	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
GJB6	TMEM60	psi-mi:“MI:0915”(physical association)	0.560
GJB6	VMA21	psi-mi:“MI:0915”(physical association)	0.400
GJB6	FUT8	psi-mi:“MI:0915”(physical association)	0.400
GJB6	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
GJB6	CHRM5	psi-mi:“MI:0915”(physical association)	0.370
GJB6	KLRC1	psi-mi:“MI:0915”(physical association)	0.000
TMEM218	GJB6	psi-mi:“MI:0915”(physical association)	0.000
GJB6	SLC10A6	psi-mi:“MI:0915”(physical association)	0.000
MS4A13	GJB6	psi-mi:“MI:0915”(physical association)	0.000
GJB6	EBP	psi-mi:“MI:0915”(physical association)	0.000
SEC22B	GJB6	psi-mi:“MI:0915”(physical association)	0.000
GPR61	GJB6	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	GJB6	psi-mi:“MI:0915”(physical association)	0.000
TMEM60	GJB6	psi-mi:“MI:0915”(physical association)	0.000
LHFPL5	GJB6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): GJB6 (Two-hybrid), KLRC1 (Two-hybrid), TMEM60 (Two-hybrid), SLC10A6 (Two-hybrid), EBP (Two-hybrid), TMEM218 (Two-hybrid), GPR61 (Two-hybrid), LHFPL5 (Two-hybrid), MS4A13 (Two-hybrid), SEC22B (Two-hybrid), GJB6 (Two-hybrid), GJB6 (Two-hybrid), VMA21 (Affinity Capture-MS), FUT8 (Affinity Capture-MS), GJB6 (Positive Genetic)

ESM2 similar proteins: A0A1B0GTI8, A6NN92, E9Q9H8, F6RWY9, O18968, O64761, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08983, P25305, P28230, P28231, P28232, P28233, P36380, P49111, P51916, P70689, P79826, Q02738, Q02739, Q0IIL2, Q13571, Q2KJA5, Q3SZ36, Q3T110, Q3TUD9, Q49LS6, Q4VV71, Q58D78, Q5E9Z5, Q5F410, Q5JW98, Q5REZ0, Q60HF7

Diamond homologs: A2VE67, A4GG66, A4GVD1, A4IFL1, A6XKM2, O18968, O54851, O57474, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08050, P08983, P14154, P16863, P16864, P17302, P18246, P18860, P18861, P21994, P23242, P25305, P28228, P28229, P28230, P28231, P28232, P28233, P28234, P28235, P28236, P29033, P29414, P29415, P33725

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

237 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	4
Uncertain significance	122
Likely benign	47
Benign	31

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1072828	NC_000013.10:g.(?_20797176)_21105944del	Pathogenic
4783767	NM_001110219.3(GJB6):c.31G>C (p.Gly11Arg)	Pathogenic
5543	NM_001110219.3(GJB6):c.14C>T (p.Thr5Met)	Pathogenic
5544	NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg)	Pathogenic
5545	NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)	Pathogenic
5547	NM_001110219.3(GJB6):c.110T>A (p.Val37Glu)	Pathogenic
815569	GRCh37/hg19 13q12.11(chr13:20668070-23029230)x1	Pathogenic
95434	NM_001110219.3(GJB6):c.261dup (p.Ala88fs)	Pathogenic
978790	Single allele	Pathogenic
1192065	NM_001110219.3(GJB6):c.176G>A (p.Gly59Glu)	Likely pathogenic
4540560	NM_001110219.3(GJB6):c.-15-1G>C	Likely pathogenic
561265	NM_001110219.3(GJB6):c.487del (p.Leu163fs)	Likely pathogenic
986211	NM_001110219.3(GJB6):c.148G>C (p.Asp50His)	Likely pathogenic

SpliceAI

303 predictions. Top by Δscore:

Variant	Effect	Δscore
13:20223491:TATCC:T	acceptor_gain	1.0000
13:20223493:TCC:T	acceptor_gain	1.0000
13:20223494:CC:C	acceptor_gain	1.0000
13:20223494:CCC:C	acceptor_gain	1.0000
13:20223495:CC:C	acceptor_gain	1.0000
13:20223496:C:CC	acceptor_gain	1.0000
13:20223496:C:T	acceptor_gain	1.0000
13:20223492:ATCC:A	acceptor_gain	0.9900
13:20223492:ATCCC:A	acceptor_gain	0.9900
13:20223493:TCCCT:T	acceptor_gain	0.9900
13:20223501:C:CT	acceptor_gain	0.9900
13:20223502:A:T	acceptor_gain	0.9900
13:20223505:C:CT	acceptor_gain	0.9900
13:20223506:A:T	acceptor_gain	0.9900
13:20229659:T:TA	donor_gain	0.9900
13:20223494:CCCT:C	acceptor_gain	0.9800
13:20223496:C:A	acceptor_gain	0.9700
13:20229670:CCCCA:C	donor_gain	0.9700
13:20230860:CATTA:C	donor_loss	0.9700
13:20230861:ATTAC:A	donor_loss	0.9700
13:20230862:TTA:T	donor_loss	0.9700
13:20230863:TA:T	donor_loss	0.9700
13:20230864:ACCTG:A	donor_loss	0.9700
13:20230865:CC:C	donor_loss	0.9700
13:20223497:T:G	acceptor_gain	0.9600
13:20223495:CCT:C	acceptor_gain	0.9500
13:20230891:A:AT	donor_gain	0.9400
13:20229671:CCCAC:C	donor_gain	0.9300
13:20230912:G:T	donor_gain	0.9300
13:20229365:C:CT	donor_gain	0.9200

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006763 (13:20228871 C>T), RS1000134479 (13:20223872 G>A), RS1000272111 (13:20223679 T>C), RS1000462704 (13:20225266 T>C,G), RS1000546320 (13:20228657 T>C), RS1000599528 (13:20224993 G>A), RS1000962914 (13:20223752 T>G), RS1001051649 (13:20228591 C>T), RS1001322265 (13:20233864 C>T), RS1001436476 (13:20234196 G>A), RS1001512871 (13:20228617 T>C), RS1001540278 (13:20223021 A>T), RS1001566125 (13:20228688 G>A,C,T), RS1001822002 (13:20223285 C>A,T), RS1002048798 (13:20228328 G>A,C)

Disease associations

OMIM: gene MIM:604418 | disease phenotypes: MIM:129500, MIM:220290, MIM:612643, MIM:612645, MIM:304400, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
Clouston syndrome	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 3B	Strong	Autosomal dominant
autosomal recessive nonsyndromic hearing loss 1B	Strong	Autosomal recessive
KID syndrome	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Refuted Evidence	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Refuted	AR
Clouston syndrome	Definitive	AD

Mondo (10): Clouston syndrome (MONDO:0007510), autosomal recessive nonsyndromic hearing loss 1A (MONDO:0009076), autosomal dominant nonsyndromic hearing loss 3B (MONDO:0012975), autosomal recessive nonsyndromic hearing loss 1B (MONDO:0012977), hearing loss disorder (MONDO:0005365), X-linked mixed hearing loss with perilymphatic gusher (MONDO:0010576), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497), KID syndrome (MONDO:0018781), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (5): Hidrotic ectodermal dysplasia (Orphanet:189), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), X-linked mixed deafness with perilymphatic gusher (Orphanet:383), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000230	Gingivitis
HP:0000365	Hearing impairment
HP:0000381	Stapes ankylosis
HP:0000399	Prelingual sensorineural hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000486	Strabismus
HP:0000491	Keratitis
HP:0000498	Blepharitis
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000572	Visual loss
HP:0000613	Photophobia
HP:0000653	Sparse eyelashes
HP:0000953	Hyperpigmentation of the skin
HP:0000966	Hypohidrosis
HP:0000968	Ectodermal dysplasia
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001072	Thickened skin
HP:0001097	Keratoconjunctivitis sicca
HP:0001155	Abnormality of the hand
HP:0001305	Dandy-Walker malformation
HP:0001320	Cerebellar vermis hypoplasia
HP:0001369	Arthritis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004729_1	Facial emotion recognition (happy faces)	3.000000e-06
GCST011928_1	Triglyceride levels x fish oil supplementation interaction (1df)	6.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement
EFO:0004530	triglyceride measurement
EFO:0600007	fish oil supplement exposure measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C567215	Deafness, Autosomal Dominant 3B (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C567134	Deafness, Autosomal Recessive 1A (supp.)
C567213	Deafness, Autosomal Recessive 1b (supp.)
C536168	Keratitis, Ichthyosis, and Deafness (KID) Syndrome (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Connexins and Pannexins

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Arsenic	decreases expression, increases abundance	2
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	2
pirinixic acid	increases expression, affects binding, increases activity	1
sodium arsenate	decreases expression, increases abundance	1
3,4-dichloroaniline	decreases expression	1
avobenzone	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Diuron	increases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1Y4	HAP1 GJB6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma