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GJC2
gap junction protein gamma 2
The GJC2 gene provides instructions for producing connexin-47, a protein vital for forming gap junctions that facilitate communication between cells in the central nervous system. The GJC2 gene encodes the connexin-47 protein, which is essential for the formation and maintenance of myelin, the protective sheath around nerve fibres.
GJC2 is located on the long (q) arm of chromosome 1, at band 1q42.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The GJC2 gene is responsible for generating connexin-47, a protein belonging to the gap junction connexin family. These proteins are fundamental for creating gap junctions, which are channels that allow for the direct transfer of nutrients, ions, and small molecules between cells. Connexin-47 is predominantly found in the brain and spinal cord, specifically within oligodendrocytes, cells critical for myelin production around nerve cells.
What the gene does
The primary role of the GJC2 gene product, connexin-47, is to form gap junctions within the central nervous system. These junctions are crucial for facilitating intercellular communication, particularly between oligodendrocytes, or between oligodendrocytes and astrocytes. Oligodendrocytes are responsible for creating myelin, a fatty substance that insulates nerve fibres and enables the rapid transmission of nerve impulses. Effective communication facilitated by connexin-47 is therefore essential for both the development and ongoing maintenance of this vital myelin sheath.
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Chromosome location
The GJC2 gene is located on chromosome 1 at position 1q42.13. This specific genomic location provides its address within the human genome.
Protein structure
The GJC2 gene encodes a protein composed of 439 amino acids. The protein includes two notable disordered regions: one spanning amino acids 108-178 and another from amino acids 364-439. These regions typically lack a fixed three-dimensional structure under physiological conditions.
Key variants
Variants within the GJC2 gene can impact the function of the connexin-47 protein, potentially leading to a range of neurological conditions. The severity and specific manifestations of these conditions can vary depending on the nature and location of the genetic change.
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 |
|---|---|---|---|---|
g.228149857A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.1134_1144del | p.Ala379fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 44 |
c.1141_1151del | p.Ser381fs | Pathogenic | ★★☆☆ | Spastic paraplegia |
c.17G>A | p.Trp6Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Leukodystrophy, hypomyelinating, 2 |
c.-20+1G>C | - | Pathogenic | ★★☆☆ | Lymphatic malformation 3 |
c.23_24delinsAA | p.Phe8Ter | Pathogenic | ★★☆☆ | Leukodystrophy, hypomyelinating, 2 |
c.392del | p.Pro131fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.591dup | p.His198fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.69_82dup | p.Leu28fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.970_971dup | p.Ala325fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
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
Mutations in the GJC2 gene are associated with several inherited conditions, primarily affecting the nervous system. These include Pelizaeus-Merzbacher-like disease type 1, which affects the brain's white matter and typically causes movement abnormalities. GJC2 variants are also linked to spastic paraplegia type 44, characterised by muscle stiffness and impaired speech, and a form of hereditary lymphoedema causing limb swelling.
No disease links recorded for this gene in our reference set.
UK clinical status
The GJC2 gene is included in several NHS England Genomic Medicine Service approved panels. These include 'Ataxia and cerebellar anomalies - childhood onset', 'Dystonia, chorea or related movement disorder, childhood onset', 'Hereditary ataxia', and 'Inherited white matter disorders', all categorised as green for their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the GJC2 gene?
The GJC2 gene provides instructions for making connexin-47, a protein that forms channels called gap junctions between cells. These junctions are critical for communication, especially in the brain and spinal cord where they support myelin formation.
What conditions are associated with GJC2 gene variants?
Variants in the GJC2 gene are associated with conditions such as Pelizaeus-Merzbacher-like disease type 1, spastic paraplegia type 44, and a type of hereditary lymphoedema. These conditions primarily affect the nervous system and motor function.
Where is the GJC2 gene active?
The GJC2 gene is primarily active in the central nervous system, specifically in oligodendrocytes. These cells are responsible for producing myelin, the protective sheath around nerve fibres that enables rapid nerve impulse transmission.
References
- Gotoh L, Inoue K, Helman G. GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease. Molecular genetics and metabolism. 2014. PMID: 24374284
- Orthmann-Murphy JL, Salsano E, Abrams CK. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain : a journal of neurology. 2009. PMID: 19056803
- Orthmann-Murphy JL, Freidin M, Fischer E. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007. PMID: 18094232
- Adam MP, Bick S, Mirzaa GM. Pelizaeus-Merzbacher-Like Disease 1. 1993. PMID: 29276893