GJB1

Last updated
GJB1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GJB1 , CMTX, CMTX1, CX32, gap junction protein beta 1
External IDs OMIM: 304040 MGI: 95719 HomoloGene: 137 GeneCards: GJB1
Orthologs
SpeciesHumanMouse
Entrez

2705

14618

Ensembl

ENSG00000169562

ENSMUSG00000047797

UniProt

P08034

P28230

RefSeq (mRNA)

NM_000166
NM_001097642

NM_008124
NM_001302496
NM_001302497
NM_001302498

RefSeq (protein)

NP_000157
NP_001091111

NP_001289425
NP_001289426
NP_001289427
NP_032150

Location (UCSC) Chr X: 71.21 – 71.23 Mb Chr X: 100.42 – 100.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. [5] Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. [6] However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system. [7]

Contents

Mutations of the GJB1 gene affecting the signalling of and trafficking through gap junctions, resulting in an inherited peripheral neuropathy called X-linked Charcot-Marie-Tooth Disease. Complications include the demyelination of oligodendrocytes and Schwann cells, causing delayed transmission rates of nerve communication in the peripheral nervous system, due to irregularities in the normal function of the cells. 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, muscle atrophy and soft tissue injuries due to delayed nerve transmission can occur. In males, due to the hemizygousity of the X-chromosome, the symptoms and issues surrounding X-linked Charcot-Marie-Tooth disease are more prevalent. [8]

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 mutations have been identified within the GJB1 gene, and it is the only known gene to be associated with this disease. [13] [14] The majority of these mutations only change a single amino acid within the protein chain, which result in a different protein being produced. Mutations within the GJB1 gene consist of novel, missense, double-missense, amino acid deletion, nonsense, frameshift, and in-frame deletions/insertions. [6] [8] [9] [15] 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 exon and three non-coding exons. GJB1 is a gap junction, beta 1 protein also identified as connexin 32, with 238 amino acids. [8] This protein contains four transmembrane domains, which when assembled form gap junctions. Each of these gap junctions consist of two hemichannels (connexions), which in turn consist of six connexin molecules (gap junction trans-membrane proteins)., [8] [9] A picture of a connexin and its connexons, showing the two hemichannels, is available here: https://commons.wikimedia.org/wiki/File:Connexon_and_connexin_structure.svg. This enables communication between Schwann cell nuclei and axons through a radial diffusion pathway. [8] As noted above, channels also form between layers of myelin. [16]

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. [8] The GJB1 protein is found in a number of organs, including the liver, kidney, pancreas and nervous system. [6] [9] In normal circumstances this protein is located in the cell membrane of Schwann cells and oligodendrocytes, specialised cells of the nervous system. [9] [17] These cells typically encapsulate nerves and are involved in the assembly and preservation of myelin, which serves to ensure reliable and rapid transmission of nerve signals. [9] [17] Typically the GJB1 protein forms channels between cells as well as through myelin to the internal Schwann cell or oligodendrocyte, allowing effective transportation and communication. [9] [17]

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. [18] The disease process involves demyelination of nerves due to impact on the Schwann cells, causing delayed transmission rates of nerve communication in the peripheral nervous system, due to irregularities in the normal function of the cells. In addition, impact on axons has been noted, While it was originally believed that axon impact was secondary to demyelination, findings in mice suggest that axon slowing may occur independent from and precede demyelination in CMT1X, due to disturbed signalling between axons and glia as well as disturbances in glial support to axons. [19]

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, muscle atrophy and soft tissue injuries due to delayed nerve transmission can occur. In males, due to the hemizygosity of the X-chromosome, the symptoms and issues surrounding X-linked Charcot-Marie-Tooth disease are more prevalent. [8]

Approximately four hundred mutations of the GJB1 gene have been identified in people with X-linked Charcot-Marie-Tooth disease (CMTX). [17] CMTX is predominantly classified with symptoms related to muscle weakness and sensory problems, especially in the outer extremities of the limbs. [9] CMTX is the second most common type of CMT (about 10% of all patients) and is transmitted as an x-linked dominant trait. [8] It is categorised by the lack of male-to-male transmission of the mutated GJB1 gene and the differences in severity between heterozygous women and hemizygous men, with the later being more severely affected. [13]

Most of the mutations of the GJB1 gene switch or change a single amino acid in the gap junction (connexin-32) protein, although some may result in a protein of irregular size. [8] [13] [15] [17] Some of these mutations also cause hearing loss in patients with CMTX. [17] Currently it is unknown how the mutations of the GJB1 gene lead to these specific features of Charcot-Marie-Tooth disease, however it is theorised that the cause is due to the demyelination of nerve cells. [17] As a result, transmission rates of nerve communication in the peripheral nervous system are delayed, which in turn would cause irregularities in the normal function of Schwann cells. [17]

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 central nervous system. [6] [17] These abnormalities whilst not presenting any symptoms were identified through nerve impulse and imaging studies, and are believed to also be caused through mutations on the GJB1 gene. [17]

Diagnosis/testing

Historically CMTX could only be diagnosed through symptoms or measurement of the speed of nerve impulses. With the creation of genetic testing, 90% of CMTX cases are now diagnosed using the mutations of the GJB1 (Cx32) gene. [13] The genetic screening of families has also become common after the diagnosis of CMTX in a patient, to further identify other family members that may be suffering from the disease. This screening is also used systematically by researchers to identify new mutations within the gene. [6] [14] [15]

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 orthoses and in some cases surgical treatment of skeletal deformities and soft-tissue abnormalities. [13] Surgical treatment most commonly includes osteotomies, soft-tissue surgery (including tendon transfers) and/or joint fusions. [13]

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. [13] With the development of genetic testing, it is possible to perform both prenatal and pre-implantation testing elected by the patient, when their type of mutation has been identified. [13] Results from genetic testing can then be used to prevent the transmission of this disease to their offspring.

See also

Related Research Articles

<span class="mw-page-title-main">Charcot–Marie–Tooth disease</span> Neuromuscular disease

Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

In vertebrates, most neuronal cell axons are encased in myelin. Simply put, myelin insulates axons and increases the rate at which electrical impulses are passed along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon in segments: in general, each axon is encased in multiple long myelin sheaths separated by short gaps called nodes of Ranvier.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Demyelinating disease</span> Any neurological disease in which the myelin sheath of neurons is damaged

A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.

<span class="mw-page-title-main">Polyneuropathy</span> Medical condition

Polyneuropathy is damage or disease affecting peripheral nerves in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may progress to the arms and legs and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy, including diabetes and some types of Guillain–Barré syndrome.

<span class="mw-page-title-main">Dejerine–Sottas disease</span> Medical condition

Dejerine–Sottas disease, also known as, Dejerine–Sottas syndrome, hereditary motor and sensory polyneuropathy type III, and Charcot–Marie–Tooth disease type 3, is a hereditary neurological disorder characterized by damage to the peripheral nerves, demyelination, and resulting progressive muscle wasting and somatosensory loss. The condition is caused by mutations in various genes and currently has no known cure.

<span class="mw-page-title-main">Myelin-associated glycoprotein</span> Protein-coding gene in the species Homo sapiens

Myelin-associated glycoprotein is a type 1 transmembrane protein glycoprotein localized in periaxonal Schwann cell and oligodendrocyte membranes, where it plays a role in glial-axonal interactions. MAG is a member of the SIGLEC family of proteins and is a functional ligand of the NOGO-66 receptor, NgR. MAG is believed to be involved in myelination during nerve regeneration in the PNS and is vital for the long-term survival of the myelinated axons following myelinogenesis. In the CNS MAG is one of three main myelin-associated inhibitors of axonal regeneration after injury, making it an important protein for future research on neurogenesis in the CNS.

<span class="mw-page-title-main">Myelin protein zero</span> Protein-coding gene in the species Homo sapiens

Myelin protein zero is a single membrane glycoprotein which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease.

Myelinogenesis is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. Myelinogenesis continues throughout the lifespan to support learning and memory via neural circuit plasticity as well as remyelination following injury. Successful myelination of axons increases action potential speed by enabling saltatory conduction, which is essential for timely signal conduction between spatially separate brain regions, as well as provides metabolic support to neurons.

<span class="mw-page-title-main">Peripheral myelin protein 22</span> Protein-coding gene in the species Homo sapiens

Growth arrest-specific protein 3 (GAS-3), also called peripheral myelin protein 22 (PMP22), is a protein which in humans is encoded by the PMP22 gene.

<span class="mw-page-title-main">PRX (gene)</span> Protein-coding gene in the species Homo sapiens

Periaxin is a protein that in humans is encoded by the PRX gene.

<span class="mw-page-title-main">SH3TC2</span> Protein-coding gene in the species Homo sapiens

SH3 domain and tetratricopeptide repeats-containing protein 2 is a protein that in humans is encoded by the SH3TC2 gene. It is believed to be expressed in the Schwann cells that wrap the myelin sheath around nerves.

<span class="mw-page-title-main">Hereditary motor and sensory neuropathy</span> Medical condition

Hereditary motor and sensory neuropathies (HMSN) is a name sometimes given to a group of different neuropathies which are all characterized by their impact upon both afferent and efferent neural communication. HMSN are characterised by atypical neural development and degradation of neural tissue. The two common forms of HMSN are either hypertrophic demyelinated nerves or complete atrophy of neural tissue. Hypertrophic condition causes neural stiffness and a demyelination of nerves in the peripheral nervous system, and atrophy causes the breakdown of axons and neural cell bodies. In these disorders, a patient experiences progressive muscle atrophy and sensory neuropathy of the extremities.

Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to describe any of the types of this disease which inhibit sensation.

<span class="mw-page-title-main">Hereditary neuropathy with liability to pressure palsy</span> Medical condition

Hereditary neuropathy with liability to pressure palsy (HNPP) is a peripheral neuropathy, a condition that affects the nerves. Pressure on the nerves can cause tingling sensations, numbness, pain, weakness, muscle atrophy and even paralysis of the affected area. In normal individuals, these symptoms disappear quickly, but in sufferers of HNPP even a short period of pressure can cause the symptoms to occur. Palsies can last from minutes or days to weeks or even months.

Anti-MAG peripheral neuropathy is a specific type of peripheral neuropathy in which the person's own immune system attacks cells that are specific in maintaining a healthy nervous system. As these cells are destroyed by antibodies, the nerve cells in the surrounding region begin to lose function and create many problems in both sensory and motor function. Specifically, antibodies against myelin-associated glycoprotein (MAG) damage Schwann cells. While the disorder occurs in only 10% of those afflicted with peripheral neuropathy, people afflicted have symptoms such as muscle weakness, sensory problems, and other motor deficits usually starting in the form of a tremor of the hands or trouble walking. There are, however, multiple treatments that range from simple exercises in order to build strength to targeted drug treatments that have been shown to improve function in people with this type of peripheral neuropathy.

<span class="mw-page-title-main">GJC3</span> Protein-coding gene in the species Homo sapiens

Gap junction gamma-3, also known as connexin-29 (Cx29) or gap junction epsilon-1 (GJE1), is a protein that in humans is encoded by the GJC3 gene.

Roussy–Lévy syndrome, also known as Roussy–Lévy areflexic dystasia, is a rare disorder of humans that results in progressive muscle wasting. It is caused by mutation the s that code for proteins necessary for the functioning of the myelin sheath of the, affecting the conductance of nerve signals and resulting in loss of muscles' ability to move.

Classifications of Charcot–Marie–Tooth disease refers to the types and subtypes of Charcot–Marie–Tooth disease (CMT), a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. CMT is a result of genetic mutations in a number of genes.

X-linked Charcot–Marie–Tooth disease is a group of genetic disorders and a type of Charcot–Marie–Tooth disease characterized by sensory loss associated with muscle weakness and atrophy alongside many other symptoms.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000169562 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000047797 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Corcos IA, Lafrenière RG, Begy CR, Loch-Caruso R, Willard HF, Glover TW (June 1992). "Refined localization of human connexin32 gene locus, GJB1, to Xq13.1". Genomics. 13 (2): 479–480. doi:10.1016/0888-7543(92)90278-Z. hdl: 2027.42/30018 . PMID   1319395.
  6. 1 2 3 4 5 Online Mendelian Inheritance in Man (OMIM): 304040
  7. ↑ Sargiannidou I, Vavlitou N, Aristodemou S, Hadjisavvas A, Kyriacou K, Scherer SS, Kleopa KA (April 2009). "Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects". The Journal of Neuroscience. 29 (15): 4736–4749. doi:10.1523/JNEUROSCI.0325-09.2009. PMC   2721059 . PMID   19369543.
  8. 1 2 3 4 5 6 7 8 9 Gonzaga-Jauregui C, Zhang F, Towne CF, Batish SD, Lupski JR (October 2010). "GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot-Marie-Tooth disease". Neurogenetics. 11 (4): 465–470. doi:10.1007/s10048-010-0247-4. PMC   4222676 . PMID   20532933.
  9. 1 2 3 4 5 6 7 8 9 Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL, et al. (December 1993). "Connexin mutations in X-linked Charcot-Marie-Tooth disease". Science. 262 (5142): 2039–2042. Bibcode:1993Sci...262.2039B. doi:10.1126/science.8266101. PMID   8266101.
  10. ↑ "Entrez Gene: GJB1 gap junction protein, beta 1, 32kDa".
  11. ↑ Kleopa et al., How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?, supra.
  12. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–676. doi: 10.1111/j.1755-148X.2008.00505.x . PMID   19067971.
  13. 1 2 3 4 5 6 7 8 9 Abrams CK (2020). "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes". In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Ledbetter N, Mefford HC, Smith RJ, Stephens K, Bird TD (eds.). GeneReviews®. University of Washington, Seattle. PMID   20301548.
  14. 1 2 Takashima H, Bondurand N, Habermann H, Karadimas C, Szigeti K. "GJB1 - gap junction protein, beta 1, 32kDa, Homo sapiens". Wikigenes.
  15. 1 2 3 Ressot C, Latour P, Blanquet-Grossard F, Sturtz F, Duthel S, Battin J, et al. (August 1996). "X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene". Human Genetics. 98 (2): 172–175. doi:10.1007/s004390050183. PMID   8698335. S2CID   8712811.
  16. ↑ 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/
  17. 1 2 3 4 5 6 7 8 9 10 "GJB1 gene". Genetics Home Reference. US National Library of Medicine.
  18. ↑ Muscular Dystrophy Association, "Charcot-Marie-Tooth Disease (CMT): CMTX, at https://www.mda.org/disease/charcot-marie-tooth/types/cmtx
  19. ↑ Kleopa KA, Abrams CK, Scherer SS (December 2012). "How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease?". Brain Research. 1487: 198–205. doi:10.1016/j.brainres.2012.03.068. PMC   3488165 . PMID   22771394.
  20. ↑ Abrams CK, Goman M, Wong S, Scherer SS, Kleopa KA, Peinado A, Freidin MM (January 2017). "Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations". Scientific Reports. 7 (1): 40166. Bibcode:2017NatSR...740166A. doi:10.1038/srep40166. PMC   5223219 . PMID   28071741.

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