GJC3

Summary

GJC3 (gap junction protein gamma 3, HGNC:17495) is a protein-coding gene on chromosome 7q22.1, encoding Gap junction gamma-3 protein (Q8NFK1). 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.

This gene encodes a gap junction protein. The encoded protein, also known as a connexin, plays a role in formation of gap junctions, which provide direct connections between neighboring cells. Mutations in this gene have been reported to be associated with nonsyndromic hearing loss.

Source: NCBI Gene 349149 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_181538

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17495
Approved symbol	GJC3
Name	gap junction protein gamma 3
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CX30.2, CX29
Ensembl gene	ENSG00000176402
Ensembl biotype	protein_coding
OMIM	611925
Entrez	349149

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000312891

RefSeq mRNA: 1 — MANE Select: NM_181538 NM_181538

CCDS: CCDS34697

Canonical transcript exons

ENST00000312891 — 2 exons

Exon	Start	End
ENSE00001231504	99923266	99923603
ENSE00001231513	99928840	99929620

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 84.70.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibial nerve	UBERON:0001323	84.70	gold quality
body of pancreas	UBERON:0001150	80.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.52	gold quality
minor salivary gland	UBERON:0001830	76.25	gold quality
saliva-secreting gland	UBERON:0001044	75.78	gold quality
sural nerve	UBERON:0015488	74.32	gold quality
thoracic mammary gland	UBERON:0005200	73.16	gold quality
pancreas	UBERON:0001264	70.96	gold quality
prostate gland	UBERON:0002367	70.62	gold quality
skin of leg	UBERON:0001511	67.94	gold quality
zone of skin	UBERON:0000014	66.05	gold quality
liver	UBERON:0002107	64.67	gold quality
right lobe of liver	UBERON:0001114	64.63	gold quality
placenta	UBERON:0001987	64.34	gold quality
skin of abdomen	UBERON:0001416	63.83	gold quality
subcutaneous adipose tissue	UBERON:0002190	62.50	gold quality
body of stomach	UBERON:0001161	62.04	gold quality
adipose tissue	UBERON:0001013	60.40	gold quality
fundus of stomach	UBERON:0001160	59.49	gold quality
substantia nigra	UBERON:0002038	59.24	gold quality
stomach	UBERON:0000945	58.87	gold quality
tonsil	UBERON:0002372	58.42	gold quality
right lung	UBERON:0002167	57.96	gold quality
omental fat pad	UBERON:0010414	57.74	gold quality
testis	UBERON:0000473	55.84	gold quality
left testis	UBERON:0004533	55.78	gold quality
left coronary artery	UBERON:0001626	55.45	gold quality
putamen	UBERON:0001874	55.45	gold quality
right testis	UBERON:0004534	55.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	8.03
E-ANND-3	yes	4.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TBX3

miRNA regulators (miRDB)

24 targeting GJC3, 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-12118	100.00	65.88	1270
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-4450	98.26	68.35	725
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-616-3P	96.82	66.99	784
HSA-MIR-675-3P	95.77	69.27	675

Literature-anchored findings (GeneRIF, showing 9)

• Cx31.3 is localized to the gray matter along small myelinated fibers and is co-expressed with Cx32 in oligodendrocytes. (PMID:18353664)
• We suggest that the c.[43C–>G(+)230G–>C] compound heterozygous variant of Cx29 may be a risk factor for the development of hearing loss in Taiwanese. (PMID:19657183)
• Data show that the p.E269D missense mutation resulted in accumulation of the Cx29 mutant protein in the endoplasmic reticulum rather than in the cytoplasmic membrane. (PMID:19876648)
• Mutations in the Cx29 gene do not play a role in the causation of non syndromic hearing impairment in Indian population. (PMID:20632892)
• The connexin30.2/CX31.3 shares functional properties with pannexin (hemi) channels rather than gap junction channels of other Connexins. (PMID:21480002)
• Although p.R15G and p.L23H mutants do not decrease the trafficking of CX proteins, mutations in GJC3 genes result in a loss of hemichannel function of CX30.2/CX31.3 protein, possibly causing hearing loss. (PMID:23179405)
• Based on these findings, we suggest that p.W77S mutant has a dominant negative effect on the formation and function of the gap junction. These results give a novel molecular elucidation for the mutation of GJC3 in the development of hearing loss. (PMID:28367085)
• GJB4 and GJC3 variants in non-syndromic hearing impairment in Ghana. (PMID:32524838)
• Pelizaeus-Merzbacher-Like Disease 1 Caused by a Novel Mutation in GJC2 Gene: A Case Report. (PMID:34840390)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gjc3	ENSMUSG00000056966
rattus_norvegicus	Gjc3	ENSRNOG00000001329

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), 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 gamma-3 protein — Q8NFK1 (reviewed: Q8NFK1)

Alternative names: Connexin-30.2, Connexin-31.3, Gap junction epsilon-1 protein

All UniProt accessions (1): Q8NFK1

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.

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

Tissue specificity. CNS specific. Expression is restricted to brain, spinal cord, and sciatic nerve. According to PubMed:12881038, expression is abundant in skeletal muscle, liver, and heart, and to a minor degree in pancreas and kidney.

Similarity. Belongs to the connexin family. Gamma-type subfamily.

RefSeq proteins (1): NP_853516* (*=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 (27 total): helix 9, topological domain 5, transmembrane region 4, turn 3, strand 3, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6L3T	ELECTRON MICROSCOPY	2.34
6L3U	ELECTRON MICROSCOPY	2.53
6L3V	ELECTRON MICROSCOPY	2.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFK1-F1	75.71	0.43

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 77 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_GROWTH, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_COMMUNICATION_INVOLVED_IN_CARDIAC_CONDUCTION, GOBP_ENSHEATHMENT_OF_NEURONS, GOBP_CELL_COMMUNICATION_BY_ELECTRICAL_COUPLING, GOBP_ORGAN_GROWTH, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION, GOBP_HEART_PROCESS, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOCC_CELL_CELL_JUNCTION, GOBP_CARDIAC_CONDUCTION, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (5): cell-cell signaling (GO:0007267), sensory perception of sound (GO:0007605), myelination (GO:0042552), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (3): gap junction channel activity (GO:0005243), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): connexin complex (GO:0005922), myelin sheath (GO:0043209), plasma membrane (GO:0005886), gap junction (GO:0005921), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cellular anatomical structure	2
cell communication	1
signaling	1
sensory perception of mechanical stimulus	1
axon ensheathment	1
transport	1
wide pore channel activity	1
protein binding	1
binding	1
gap junction	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJC3	KCNA2	P16389	827
GJC3	AP1S1	P61966	788
GJC3	GJA5	P36382	487
GJC3	GJC1	P36383	470
GJC3	PBXIP1	Q96AQ6	430
GJC3	PANX1	Q96RD7	428
GJC3	PANX2	Q96RD6	385
GJC3	ZMAT2	Q96NC0	382
GJC3	PMVK	Q15126	379
GJC3	PANX3	Q96QZ0	370
GJC3	ERMN	Q8TAM6	364
GJC3	LGI4	Q8N135	360
GJC3	OR10H3	O60404	356
GJC3	KCNA1	Q09470	348
GJC3	AZGP1	P25311	347

IntAct

7 interactions, top by confidence:

A	B	Type	Score
MS4A13	GJC3	psi-mi:“MI:0915”(physical association)	0.560
STX7	GJC3	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	GJC3	psi-mi:“MI:0915”(physical association)	0.000
STX7	GJC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): GJC3 (Two-hybrid), MS4A13 (Two-hybrid)

ESM2 similar proteins: A3KN25, A4IFL1, O18968, O70491, O75712, O95377, P08033, P25305, P28230, P28231, P28232, P28233, P28234, P28235, P29414, P33725, P35212, P36380, P36382, P41987, Q01231, Q02738, Q02739, Q03190, Q08DF2, Q0V8E7, Q0VCR2, Q29RK8, Q4QR83, Q58D78, Q5E9Z5, Q5R7B4, Q60HF7, Q64448, Q6WGK6, Q7M734, Q80VM9, Q866T7, Q8BSD4, Q8CE93

Diamond homologs: A2VE67, A3KN25, A4GG66, A4GVD1, A4IFL1, A6XKM2, O18968, O57474, 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, P35212, P36381

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

644 predictions. Top by Δscore:

Variant	Effect	Δscore
6:142133846:ACAGG:A	acceptor_loss	1.0000
6:142133847:CAGG:C	acceptor_loss	1.0000
6:142133849:G:GA	acceptor_loss	1.0000
6:142133193:GATGT:G	donor_gain	0.9900
6:142133194:ATGT:A	donor_gain	0.9900
6:142133194:ATGTG:A	donor_loss	0.9900
6:142133195:TGT:T	donor_gain	0.9900
6:142133195:TGTGT:T	donor_loss	0.9900
6:142133196:GT:G	donor_gain	0.9900
6:142133196:GTG:G	donor_gain	0.9900
6:142133196:GTGTA:G	donor_loss	0.9900
6:142133197:TGT:T	donor_gain	0.9900
6:142133198:G:GA	donor_loss	0.9900
6:142133198:G:GG	donor_gain	0.9900
6:142133199:TA:T	donor_loss	0.9900
6:142133200:AA:A	donor_loss	0.9900
6:142133837:A:AG	acceptor_gain	0.9900
6:142133838:A:G	acceptor_gain	0.9900
6:142133840:A:G	acceptor_gain	0.9900
6:142133843:A:AG	acceptor_gain	0.9900
6:142133844:T:G	acceptor_gain	0.9900
6:142133849:GGTT:G	acceptor_gain	0.9900
6:142133849:GGTTA:G	acceptor_gain	0.9900
7:99923605:T:C	acceptor_gain	0.9900
7:99923608:T:TC	acceptor_gain	0.9900
7:99928439:A:AC	donor_gain	0.9900
7:99928440:C:CC	donor_gain	0.9900
6:142133193:G:GT	donor_gain	0.9800
6:142133198:GTA:G	donor_gain	0.9800
6:142133201:AG:A	donor_loss	0.9800

AlphaMissense

1787 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:99929469:A:C	F51C	0.958
7:99929468:G:C	F51L	0.952
7:99929468:G:T	F51L	0.952
7:99929470:A:G	F51L	0.952
7:99929024:G:C	S199R	0.910
7:99929024:G:T	S199R	0.910
7:99929026:T:G	S199R	0.910
7:99929357:G:C	S88R	0.910
7:99929357:G:T	S88R	0.910
7:99929359:T:G	S88R	0.910
7:99929429:G:C	C64W	0.895
7:99929082:C:G	C180S	0.885
7:99929083:A:T	C180S	0.885
7:99929393:G:C	F76L	0.883
7:99929393:G:T	F76L	0.883
7:99929395:A:G	F76L	0.883
7:99929463:C:G	C53S	0.882
7:99929464:A:T	C53S	0.882
7:99929442:C:G	C60S	0.879
7:99929443:A:T	C60S	0.879
7:99929533:C:G	G30R	0.873
7:99929533:C:T	G30R	0.873
7:99929430:C:T	C64Y	0.865
7:99929361:G:C	P87R	0.862
7:99929178:T:A	E148V	0.861
7:99929426:G:C	F65L	0.854
7:99929426:G:T	F65L	0.854
7:99929428:A:G	F65L	0.854
7:99929361:G:T	P87H	0.853
7:99929033:A:C	F196L	0.849

dbSNP variants (sampled 300 via entrez): RS1000151093 (7:99925355 G>T), RS1000336889 (7:99931221 G>A), RS1001102546 (7:99926731 A>G), RS1001156367 (7:99926909 A>G), RS1002101702 (7:99927815 G>T), RS1003148176 (7:99926471 A>G), RS1003464720 (7:99922962 G>A), RS1003859634 (7:99930551 T>C), RS1004062579 (7:99924461 G>A,C), RS1004299440 (7:99928003 G>A), RS1004636100 (7:99926893 G>A), RS1004862021 (7:99932182 G>A), RS1005123758 (7:99932453 T>C,G), RS1005475940 (7:99926205 G>A,C), RS1005617875 (7:99927498 C>T)

Disease associations

OMIM: gene MIM:611925 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_259	Refractive error	3.000000e-16

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

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Catechin	increases expression, affects cotreatment	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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