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GJB1
gap junction protein beta 1
The GJB1 gene provides instructions for producing connexin 32, a protein vital for cellular communication, particularly in peripheral nerves, where it influences myelin formation and nerve impulse transmission. GJB1 encodes the connexin 32 protein, which forms gap junctions allowing cells to communicate by passing small molecules and ions.
GJB1 is located on the long (q) arm of chromosome X, at band Xq13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The GJB1 gene, also known as connexin 32 (Cx32), is responsible for producing a protein that forms gap junctions. These junctions are essential for direct communication between neighbouring cells, facilitating the passage of charged particles, nutrients, and signalling molecules. This intercellular communication is particularly critical in the nervous system.
Connexin 32 plays a significant role in the function of peripheral nerves, which transmit signals between the brain, spinal cord, muscles, and sensory cells. Variants in GJB1 can disrupt this crucial function, leading to various neurological conditions.
What the gene does
The GJB1 gene directs the synthesis of connexin 32, a member of the connexin protein family. These proteins assemble to create gap junctions, which are specialised channels that connect the cytoplasm of adjacent cells. Through these channels, ions, small molecules, and nutrients can pass directly from one cell to another, enabling rapid cellular communication and coordination.
Connexin 32 is particularly abundant in the peripheral nervous system, specifically in Schwann cells, and in the central nervous system within oligodendrocytes. Both cell types are responsible for producing myelin, a fatty sheath that insulates nerve fibres and enables efficient transmission of nerve impulses. In Schwann cells, connexin 32 forms channels within the myelin layers, allowing for communication between the outer parts of the myelin sheath and the inner cell components. This function is vital for maintaining the integrity and proper function of peripheral nerves.
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Chromosome location
The GJB1 gene is located on the long (q) arm of the X chromosome at position 13.1, designated as Xq13.1. This genomic location means that GJB1 is an X-linked gene, influencing its inheritance patterns. The gene spans approximately 4.5 kilobases of DNA.
Protein structure
The GJB1 gene produces a protein called connexin 32, which consists of 283 amino acids. This protein is a transmembrane protein, meaning it spans the cell membrane. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Hundreds of different genetic variants have been identified within the GJB1 gene. These variants can include small changes in DNA building blocks (point mutations), as well as small insertions or deletions. When these variants alter the structure or function of the connexin 32 protein, they can interfere with normal cellular communication, particularly in the nervous system.
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.184A>C | p.Ser62Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary neuropathy or pain disorder |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.230G>A | p.Trp77Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease X-linked dominant 1 |
c.260C>G | p.Pro87Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease X-linked dominant 1 |
c.287C>G | p.Ala96Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.292C>T | p.Gln98Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.450del | p.Met150fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.462T>A | p.Tyr154Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease X-linked dominant 1 |
c.46C>G | p.His16Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Peripheral neuropathy |
c.513C>G | p.Tyr171Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
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 GJB1 gene are primarily associated with Charcot-Marie-Tooth disease. This is a group of inherited neurological disorders that affect the peripheral nerves, leading to symptoms such as muscle weakness and sensory loss, often beginning in the feet and lower legs before progressing to the hands and arms.
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UK clinical status
The GJB1 gene is well-recognised within the UK's NHS Genomic Medicine Service. It is listed on several green-rated (clinically actionable) panels in PanelApp UK, including 'Hereditary neuropathy', 'Hereditary neuropathy or pain disorder (R78)', 'Inherited white matter disorders', 'Leukodystrophy, adult onset (R62)', and 'White matter disorders and cerebral calcification - childhood onset'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the GJB1 gene?
The GJB1 gene provides instructions for making connexin 32, a protein that forms gap junctions. These junctions allow direct communication between neighbouring cells, facilitating the passage of small molecules and ions, which is crucial for nerve function.
What condition is most commonly associated with GJB1 gene variants?
Variants in the GJB1 gene are most commonly associated with Charcot-Marie-Tooth disease. This is an inherited neurological disorder affecting peripheral nerves, leading to muscle weakness and sensory loss, particularly in the extremities.
Why is GJB1 important in the nervous system?
GJB1 is important in the nervous system because its protein, connexin 32, is found in Schwann cells and oligodendrocytes. These cells produce myelin, which insulates nerve fibres. The protein forms channels within myelin layers, essential for maintaining nerve health and efficient nerve impulse transmission.
References
- Wang Y, Yin F. A Review of X-linked Charcot-Marie-Tooth Disease. Journal of child neurology. 2016. PMID: 26385972
- Abrams CK, Freidin M. GJB1-associated X-linked Charcot-Marie-Tooth disease, a disorder affecting the central and peripheral nervous systems. Cell and tissue research. 2015. PMID: 25370202
- Kleopa KA, Sargiannidou I. Connexins, gap junctions and peripheral neuropathy. Neuroscience letters. 2015. PMID: 25449862
- Scherer SS, Kleopa KA. X-linked Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS. 2012. PMID: 23279425
- Sargiannidou I, Markoullis K, Kleopa KA. Molecular mechanisms of gap junction mutations in myelinating cells. Histology and histopathology. 2010. PMID: 20607661
- Sargiannidou I, Vavlitou N, Aristodemou S. Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009. PMID: 19369543
- Wang HL, Chang WT, Yeh TH. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiology of disease. 2004. PMID: 15006706
- Ressot C, Bruzzone R. Connexin channels in Schwann cells and the development of the X-linked form of Charcot-Marie-Tooth disease. Brain research. Brain research reviews. 2000. PMID: 10751670