Normal Function
The GJC2 gene provides instructions for making a protein called connexin-47. This protein is a member of the gap junction connexin family, a group of proteins that form channels called gap junctions between cells. Gap junctions allow for the transport of nutrients, charged particles (ions), and small molecules between cells.
Connexin-47 is produced in the brain and spinal cord (central nervous system), specifically in cells called oligodendrocytes, which help coat nerve cells with a protective layer called myelin. Myelin is a fatty substance that insulates nerve fibers and promotes the rapid transmission of nerve impulses.
Connexin-47 forms gap junctions that facilitate communication between oligodendrocytes or between oligodendrocytes and another type of nervous system cell called astrocytes. Communication between these cells is necessary for the formation and maintenance of myelin.
Health Conditions Related to Genetic Changes
Pelizaeus-Merzbacher-like disease type 1
At least 30 mutations in the GJC2 gene have been found to cause Pelizaeus-Merzbacher-like disease type 1. This condition affects the nervous system's white matter, which consists of nerve fibers covered by myelin. Individuals with Pelizaeus-Merzbacher-like disease type 1 have neurological problems that typically cause movement abnormalities and less frequently, vision problems.
Two GJC2 gene mutations that appear in up to one-third of people with this condition occur in an area of the GJC2 gene called the promoter region, which helps control the production of connexin-47. These mutations reduce the production of connexin-47, leading to a decrease in gap junction formation. Other GJC2 gene mutations prevent the connexin-47 protein from reaching the cell membrane where it is needed to form gap junctions. Still other GJC2 gene mutations decrease the function of the protein in the gap junction, reducing the overall efficacy of the channel.
All of the GJC2 gene mutations that cause this condition affect both copies of the gene in each cell. They disrupt the communication between nerve cells that normally occurs at gap junctions and impair myelin formation. These changes lead to nerve damage that impairs nervous system function, resulting in the signs and symptoms of Pelizaeus-Merzbacher-like disease type 1.
More About This Health ConditionOther disorders
Mutations in the GJC2 gene are also associated with a neurological disorder called spastic paraplegia type 44 and a form of hereditary lymphedema that causes abnormal swelling of the limbs.
Spastic paraplegia type 44 is characterized by muscle stiffness (spasticity), paralysis of the upper limbs (paraplegia), impaired speech (dysarthria), and mild intellectual disability. These signs and symptoms typically begin in childhood. Spastic paraplegia type 44 is caused by a specific GJC2 gene mutation that is present in both copies of the gene in each cell. This mutation replaces the protein building block (amino acid) isoleucine with the amino acid methionine at position 33 in the protein (written as Ile33Met or I33M). This change reduces but does not eliminate connexin-47 activity. As a result, gap junctions have some function, which may explain why spastic paraplegia type 44 has similar features to Pelizaeus-Merzbacher-like disease type 1 (described above) but is less severe.
Hereditary lymphedema caused by GJC2 gene mutations is a condition that affects the normal function of the lymphatic system. The lymphatic system produces and transports lymph fluid and immune cells throughout the body. Impaired transport of lymph fluid resulting in its accumulation can cause swelling (lymphedema). Individuals with hereditary lymphedema can have swelling from birth or develop it later in life. The lymphedema typically begins in the legs and often involves the arms over time. Hereditary lymphedema is caused by mutations in one copy of the GJC2 gene, but it is unclear what role the GJC2 gene plays in the lymphatic system and how mutations cause this condition.
Other Names for This Gene
- connexin-46.6
- connexin-47
- CX46.6
- Cx47
- gap junction alpha-12 protein
- gap junction gamma-2 protein
- gap junction protein, gamma 2, 47kDa
- GJA12
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Gotoh L, Inoue K, Helman G, Mora S, Maski K, Soul JS, Bloom M, Evans SH, Goto YI, Caldovic L, Hobson GM, Vanderver A. GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease. Mol Genet Metab. 2014 Mar;111(3):393-398. doi: 10.1016/j.ymgme.2013.12.001. Epub 2013 Dec 16. Erratum In: Mol Genet Metab. 2016 Nov;119(3):293. doi: 10.1016/j.ymgme.2016.06.011. Citation on PubMed or Free article on PubMed Central
- Nahhas N, Conant A, Orthmann-Murphy J, Vanderver A, Hobson G. Pelizaeus-Merzbacher-Like Disease 1. 2017 Dec 21 [updated 2019 Jan 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK470716/ Citation on PubMed
- Orthmann-Murphy JL, Freidin M, Fischer E, Scherer SS, Abrams CK. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. J Neurosci. 2007 Dec 19;27(51):13949-57. doi: 10.1523/JNEUROSCI.3395-07.2007. Citation on PubMed
- Orthmann-Murphy JL, Salsano E, Abrams CK, Bizzi A, Uziel G, Freidin MM, Lamantea E, Zeviani M, Scherer SS, Pareyson D. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain. 2009 Feb;132(Pt 2):426-38. doi: 10.1093/brain/awn328. Epub 2008 Dec 4. Citation on PubMed or Free article on PubMed Central
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