GJB1
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Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a
Mutations of the GJB1 gene affecting the signalling of and trafficking through gap junctions, resulting in an inherited peripheral neuropathy called X-linked
Function
Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells.[9] For a general discussion of connexin proteins, see GJB2.[10] In Schwann cells, GJB1 also forms channels that facilitate transfers between layers of the myelin. [11]
In melanocytic cells GJB1 gene expression may be regulated by MITF.[12]
Gene
The gene that encodes the human GJB1 protein is found on the X chromosome, on the long arm at position q13.1, in interval 8, from base pair 71,215,212 to base pair 71,225,215.[5][9]
Mutations
Approximately four hundred type X Charcot-Marie-Tooth causing
These mutations most commonly result in proteins that work incorrectly, less effectively, degrade faster, are not present in adequate numbers or may not function at all.Structure
The GJB1 gene is approximately 10kb in length, with one coding
Function
GJB1 functions as a radial diffusion pathway, allowing the communication and diffusion of nutrients, ions and small molecules between cells, and between layers of myelin.
Type X Charcot-Marie-Tooth disease
Mutations in the GJB1 gene can lead to a variety of changes in the Connexin 32 protein or its expression, as compared to the wild type gene. Pathogenic mutations in the gene affect signalling and trafficking of small molecules through gap junctions, resulting in disease - most notably an inherited peripheral neuropathy known as Charcot-Marie-Tooth disease, also often referred to as CMT. Despite the name, CMT does not affect the teeth; the word "tooth" refers to the name of one of the doctors who were important to its discovery. Because GJB1 is located on the X chromosome, GJB1 disease is a type of "X-linked" CMT. Multiple X-linked CMTs have now been identified, and GJB1 disease is referred to as CMT1X or CMTX1.
Unlike many other types of CMT, CMT1X is known to cause effects in the central nervous system ("CNS") as well as the peripheral nervous system.[13] However, it is believed that whether or not an individual experiences CNS effects may depend upon the specific mutation involved, and the more precise shape and function of the mutant protein in question, as some mutant GJB1 proteins have much more functionality than others.[20]
This condition leads to a number of symptoms, most commonly muscle weakness and sensory problems in the outer extremities of the limbs. As a result,
Approximately four hundred mutations of the GJB1 gene have been identified in people with X-linked Charcot-Marie-Tooth disease (CMTX).
Most of the mutations of the GJB1 gene switch or change a single
Whilst CMTX is more commonly known to affect the peripheral nervous system some cases have been reported in which there is evidence of demyelination of the
Diagnosis/testing
Historically CMTX could only be diagnosed through symptoms or measurement of the speed of nerve impulses. With the creation of
Management
Currently CMTX is an incurable condition, instead patients are evaluated and treated for symptoms caused by the disease. Treatment is limited to rehabilitative therapy, use of assistive devices such as
Genetic counseling
Due to the nature of inheritance of CMTX, affected males will pass the GJB1 gene mutation to all female children and none of their male children, whilst females who are carriers will have a 50% chance of passing on the mutation to each of their offspring.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000169562 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047797 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 1319395.
- ^ a b c d e Online Mendelian Inheritance in Man (OMIM): 304040
- PMID 19369543.
- ^ PMID 20532933.
- ^ PMID 8266101.
- ^ "Entrez Gene: GJB1 gap junction protein, beta 1, 32kDa".
- ^ Kleopa et al., How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?, supra.
- PMID 19067971.
- ^ PMID 20301548.
- ^ a b Takashima H, Bondurand N, Habermann H, Karadimas C, Szigeti K. "GJB1 - gap junction protein, beta 1, 32kDa, Homo sapiens". Wikigenes.
- ^ S2CID 8712811.
- ^ National Library of Medicine, MedlinePlus, GJB1 Gene ("The connexin-32 protein forms channels through the myelin sheath, allowing efficient transport and communication between the outer myelin layers and the interior of the Schwann cell or oligodendrocyte."), at https://medlineplus.gov/genetics/gene/gjb1/
- ^ a b c d e f g h i j "GJB1 gene". Genetics Home Reference. US National Library of Medicine.
- ^ Muscular Dystrophy Association, "Charcot-Marie-Tooth Disease (CMT): CMTX, at https://www.mda.org/disease/charcot-marie-tooth/types/cmtx
- PMID 22771394.
- PMID 28071741.
Further reading
- Harris AL, Locke D (2009). Connexins, A Guide. New York: Springer. p. 574. ISBN 978-1-934115-46-6.
- Latour P, Fabreguette A, Ressot C, Blanquet-Grossard F, Antoine JC, Calvas P, et al. (1997). "New mutations in the X-linked form of Charcot-Marie-Tooth disease". European Neurology. 37 (1): 38–42. PMID 9018031.
- Bone LJ, Deschênes SM, Balice-Gordon RJ, Fischbeck KH, Scherer SS (1997). "Connexin32 and X-linked Charcot-Marie-Tooth disease" (PDF). Neurobiology of Disease. 4 (3–4): 221–230. S2CID 1322575. Archived from the original(PDF) on 2019-03-08.
- Nelis E, Haites N, Van Broeckhoven C (1999). "Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies". Human Mutation. 13 (1): 11–28. S2CID 31130790.
- Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, et al. (January 2003). "Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients". Brain. 126 (Pt 1): 134–151. PMID 12477701.
- Sato H, Hagiwara H, Ohde Y, Senba H, Virgona N, Yano T (March 2007). "Regulation of renal cell carcinoma cell proliferation, invasion and metastasis by connexin 32 gene". The Journal of Membrane Biology. 216 (1): 17–21. S2CID 38489865.