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GJB2
gap junction protein beta 2
The GJB2 gene provides instructions for making connexin 26, a protein vital for forming gap junctions that facilitate communication between cells, particularly in the inner ear and skin. Pathogenic variants in GJB2 are a common cause of inherited hearing loss and can also be associated with certain skin disorders.
GJB2 is located on the long (q) arm of chromosome 13, at band 13q12.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The GJB2 gene, also known as connexin 26, is crucial for producing a protein involved in cell-to-cell communication. This protein forms gap junctions, which are channels that allow the transport of small molecules and ions between adjacent cells. Its function is particularly important in the inner ear for hearing and in the skin for maintaining its structure and function.
What the gene does
The GJB2 gene encodes gap junction beta 2, also referred to as connexin 26. This protein is a member of the connexin family, which forms intercellular channels known as gap junctions. These channels enable the direct passage of nutrients, ions, and small molecules between neighbouring cells, facilitating coordinated cellular activities. In the inner ear, connexin 26 plays a critical role in the recycling of potassium ions, which is essential for converting sound waves into electrical nerve impulses required for hearing. It is also thought to be important for the maturation of specific cells within the cochlea, the snail-shaped structure of the inner ear. In the skin, connexin 26 contributes to the growth, maturation, and stability of the epidermis, the skin's outermost layer.
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Chromosome location
The GJB2 gene is located on the long (q) arm of chromosome 13 at position 12.11, denoted as 13q12.11. This gene is found in a region of the genome known to contain genes important for various physiological processes.
Protein structure
The GJB2 gene produces a protein composed of 226 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the GJB2 gene can alter the function of the connexin 26 protein, leading to a range of health conditions. These genetic changes can affect how effectively gap junctions transport molecules or how the protein itself is structured. The impact of a specific variant often depends on its location within the gene and how it changes the resulting protein.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.2T>C | p.Met1Thr | Pathogenic | ★★★☆ | Nonsyndromic genetic hearing loss |
c.2T>G | p.Met1Arg | Pathogenic | ★★★☆ | Nonsyndromic genetic hearing loss |
c.3G>A | p.Met1Ile | Pathogenic | ★★★☆ | Nonsyndromic genetic hearing loss |
c.516G>C | p.Trp172Cys | Pathogenic | ★★★☆ | Nonsyndromic genetic hearing loss |
c.583A>G | p.Met195Val | Pathogenic | ★★★☆ | Nonsyndromic genetic hearing loss |
c.155_158del | p.Val52fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant keratitis-ichthyosis-hearing loss syndrome |
c.389G>T | p.Gly130Val | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.614T>C | p.Leu205Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 1A |
c.630_634del | p.Cys211fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 1A |
c.93del | p.Arg32fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the GJB2 gene are primarily associated with various forms of hearing loss. These include non-syndromic hearing loss (DFNB1), which is a common cause of congenital deafness, and GJB2-related deafness (mild/moderate). In some cases, GJB2 variants can also be linked to conditions that affect the skin, such as palmoplantar keratoderma with deafness, and hystrix-like ichthyosis with deafness, which involve skin abnormalities alongside hearing impairment.
- Deafness (GJB2-related, mild/moderate)
- Non-syndromic hearing loss (DFNB1) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic GJB2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The GJB2 gene is included in several UK NHS national genomic testing panels, highlighting its clinical significance. It is listed as 'green' (genes with strong evidence for association with disease) on PanelApp UK for Monogenic hearing loss (R67), Ichthyosis and erythrokeratoderma (R165), Palmoplantar keratoderma and erythrokeratodermas, and Palmoplantar keratodermas (R166). This indicates that variants in GJB2 are routinely assessed in the UK for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the GJB2 gene responsible for?
The GJB2 gene provides instructions for making the connexin 26 protein, which forms channels called gap junctions. These channels are crucial for transporting nutrients, ions, and small molecules between cells, particularly in the inner ear for hearing and in the skin.
How does the GJB2 gene affect hearing?
In the inner ear, the connexin 26 protein helps recycle potassium ions. This process is essential for converting sound waves into the electrical signals that the brain interprets as sound, making GJB2 vital for normal hearing function.
What conditions are associated with GJB2 gene variants?
Variants in the GJB2 gene are most commonly associated with non-syndromic hearing loss. They can also contribute to certain syndromic conditions that include both hearing loss and skin abnormalities, such as palmoplantar keratoderma with deafness.
References
- Tsukada K, Nishio SY, Hattori M. Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. The Annals of otology, rhinology, and laryngology. 2015. PMID: 25999548
- Sanchez HA, Verselis VK. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss. Frontiers in cellular neuroscience. 2014. PMID: 25386120
- Marlin S, Feldmann D, Blons H. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Archives of otolaryngology--head & neck surgery. 2005. PMID: 15967879
- Adam MP, Bick S, Mirzaa GM. GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. 1993. PMID: 20301449