GJA1 (Connexin 43): Structure, Function, and Clinical Significance
A comprehensive overview of the GJA1 gene, its protein product connexin 43, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | GJA1 |
|---|---|
| Full Name | Gap junction protein alpha 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 6q22.31 |
| NCBI Gene ID | 2697 ncbi.nlm.nih.gov/gene/2697 |
| Ensembl ID | ENSG00000152661 |
| UniProt ID | P17302 |
| OMIM ID | 121014 |
| HGNC ID | 4274 |
| Aliases | CX43, ODDD, GJAL, HLHS1, AVSD3, EKVP, CMDR |
Description
The GJA1 gene encodes connexin 43 (Cx43), a member of the connexin family of proteins that form gap junction channels. These channels facilitate direct intercellular communication by allowing the passage of ions, small metabolites, and signaling molecules between adjacent cells. Cx43 is widely expressed in various tissues, including the heart, brain, skin, and bone, and plays critical roles in cardiac conduction, embryonic development, and tissue homeostasis. Mutations in GJA1 are associated with several inherited disorders, including oculodentodigital dysplasia (ODDD), cardiac arrhythmias, and congenital heart defects.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Oculodentodigital dysplasia (ODDD) | Missense or frameshift mutations in GJA1 lead to altered gap junction function, often with dominant-negative or gain-of-function effects, disrupting normal cell-cell communication during development. | ClinVar, OMIM |
| Atrioventricular septal defect (AVSD) | GJA1 mutations can impair cardiac neural crest cell migration or gap junction coupling, contributing to abnormal septation of the heart. | ClinVar, OMIM |
| Hypoplastic left heart syndrome (HLHS) | Rare variants in GJA1 have been implicated in disrupted cardiac morphogenesis, possibly due to reduced Cx43 function in cardiac progenitor cells. | ClinVar, OMIM |
| Cardiac arrhythmias (e.g., atrial fibrillation) | Altered Cx43 expression or function can slow conduction velocity and increase susceptibility to re-entrant arrhythmias. | ClinVar, PubMed (via OMIM) |
| Syndactyly and limb abnormalities | GJA1 mutations affect limb development, likely through impaired gap junction communication in the apical ectodermal ridge. | OMIM, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | High (e.g., 100+ nTPM) | High |
| Brain | Moderate (e.g., 50-100 nTPM) | Moderate |
| Skin | Moderate (e.g., 30-50 nTPM) | Moderate |
| Bone | Moderate (e.g., 20-40 nTPM) | Moderate |
| Lung | Low (e.g., <20 nTPM) | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cardiomyocytes | High | Key for electrical coupling |
| Endothelial cells | Moderate | Involved in vascular function |
| Fibroblasts | Moderate | Wound healing and tissue remodeling |
| Osteoblasts | Moderate | Bone formation |
| Neurons | Low | Limited expression in mature neurons |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Gly21Arg | Missense | Rare (found in ODDD) | Dominant-negative effect on gap junction formation |
| p.Arg76Trp | Missense | Rare (ODDD) | Altered channel gating and trafficking |
| p.Val96Met | Missense | Rare (ODDD) | Impaired gap junction assembly |
| p.Ile130Thr | Missense | Rare (ODDD) | Dominant-negative effect |
| p.Arg202Gln | Missense | Rare (ODDD) | Reduced channel conductance |
| p.Gly138Arg | Missense | Rare (ODDD) | Impaired trafficking to cell membrane |
| c.932delC | Frameshift | Rare (ODDD) | Truncated protein, loss of function |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., frameshift or nonsense) reduce Cx43 protein levels or channel function, leading to impaired intercellular communication. These are often associated with recessive forms of ODDD or cardiac defects.
Gain of Function (GOF)
Some missense mutations may produce channels with altered permeability or gating, resulting in increased or aberrant ionic flux, potentially contributing to arrhythmias or skin disorders.
Dominant Negative (DN)
Most ODDD-associated mutations act in a dominant-negative manner, where the mutant protein interferes with the function of wild-type Cx43, disrupting gap junction plaque formation and channel activity.
View complete mutation data：
Gene Ontology (GO)
| • gap junction channel activity | • protein homodimerization activity |
| • cell-cell signaling | • cell communication |
| • cardiac conduction | • embryonic development |
| • response to wound healing |
Pathways
• Gap junction trafficking
• Cardiac conduction system
• Cell-cell communication
• Connexin signaling in development
Protein Summary
Connexin 43 (Cx43) is a four-pass transmembrane protein that oligomerizes into hexameric connexons (hemichannels). Two connexons from adjacent cells dock to form a complete gap junction channel, allowing direct cytoplasmic exchange of molecules up to ~1 kDa. Cx43 is dynamically regulated by phosphorylation, which modulates channel gating, trafficking, and degradation. It is essential for electrical synchronization in the heart and plays roles in cell growth, differentiation, and apoptosis. Mutations in Cx43 can lead to a spectrum of diseases, primarily affecting the heart, craniofacial development, and limbs.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GJA1 Knockout HEK293 Cell Line | EDJ-KQ2803 | Human | 2697 | Details Get a Quote |
| GJA10 Knockout HEK293 Cell Line | EDJ-KQ10169 | Human | 84694 | Details Get a Quote |
| GJA1 Knockout A-549 Cell Line | EDJ-KQ23737 | Human | 2697 | Details Get a Quote |
| GJA1 Knockout HeLa Cell Line | EDJ-KQ23738 | Human | 2697 | Details Get a Quote |
| GJA10 Knockout HeLa Cell Line | EDJ-KQ57650 | Human | 84694 | Details Get a Quote |
| GJA10 Knockout A-549 Cell Line | EDJ-KQ66148 | Human | 84694 | Details Get a Quote |
| GJA1 Knockout HCT 116 Cell Line | EDJ-KQ70310 | Human | 2697 | Details Get a Quote |
| GJA10 Knockout HCT 116 Cell Line | EDJ-KQ74575 | Human | 84694 | Details Get a Quote |
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