1TXH
46-400: 2705 14618 ENSG00000169562 ENSMUSG00000047797 P08034 P28230 NM_000166 NM_001097642 NM_008124 NM_001302496 NM_001302497 NM_001302498 NP_000157 NP_001091111 NP_001289425 NP_001289426 NP_001289427 NP_032150 Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans
92-518: 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. As noted above, channels also form between layers of myelin. 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. The GJB1 protein
138-550: A large fraction of non-coding DNA . For instance, in the human genome only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA . This can provide a practical advantage in omics -aided health care (such as precision medicine ) because it makes commercialized whole exome sequencing a smaller and less expensive challenge than commercialized whole genome sequencing . The large variation in genome size and C-value across life forms has posed an interesting challenge called
184-458: 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. Approximately four hundred mutations of
230-496: A signal-anchor sequence, with type II being targeted to the ER lumen with its C-terminal domain, while type III have their N-terminal domains targeted to the ER lumen. Type IV is subdivided into IV-A, with their N-terminal domains targeted to the cytosol and IV-B, with an N-terminal domain targeted to the lumen. The implications for the division in the four types are especially manifest at the time of translocation and ER-bound translation, when
276-482: A standard technique in developmental biology . Morpholino oligos can also be targeted to prevent molecules that regulate splicing (e.g. splice enhancers, splice suppressors) from binding to pre-mRNA, altering patterns of splicing. Common incorrect uses of the term exon are that 'exons code for protein', or 'exons code for amino-acids' or 'exons are translated'. However, these sorts of definitions only cover protein-coding genes , and omit those exons that become part of
322-446: 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 . 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)., A picture of
368-450: Is encoded by the GJB1 gene . 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 . However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system. Mutations of
414-440: Is found in a number of organs, including the liver , kidney , pancreas and nervous system . In normal circumstances this protein is located in the cell membrane of Schwann cells and oligodendrocytes , specialised cells of the nervous system. 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. Typically
460-407: Is known to cause effects in the central nervous system ("CNS") as well as the peripheral nervous system. 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. This condition leads to
506-429: Is technically difficult. There are relatively few examples of the successful refolding experiments, as for bacteriorhodopsin . In vivo , all such proteins are normally folded co-translationally within the large transmembrane translocon . The translocon channel provides a highly heterogeneous environment for the nascent transmembrane α-helices. A relatively polar amphiphilic α-helix can adopt a transmembrane orientation in
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#1732908339295552-400: Is thought that β-barrel membrane proteins come from one ancestor even having different number of sheets which could be added or doubled during evolution. Some studies show a huge sequence conservation among different organisms and also conserved amino acids which hold the structure and help with folding. Note: n and S are, respectively, the number of beta-strands and the "shear number" of
598-475: 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. 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 . Whilst CMTX is more commonly known to affect
644-641: The C-value enigma . Across all eukaryotic genes in GenBank, there were (in 2002), on average, 5.48 exons per protein coding gene. The average exon encoded 30-36 amino acids . While the longest exon in the human genome is 11555 bp long, several exons have been found to be only 2 bp long. A single-nucleotide exon has been reported from the Arabidopsis genome. In humans, like protein coding mRNA , most non-coding RNA also contain multiple exons In protein-coding genes,
690-429: The GJB1 gene have been identified in people with X-linked Charcot-Marie-Tooth disease (CMTX). CMTX is predominantly classified with symptoms related to muscle weakness and sensory problems, especially in the outer extremities of the limbs. CMTX is the second most common type of CMT (about 10% of all patients) and is transmitted as an x-linked dominant trait . It is categorised by the lack of male-to-male transmission of
736-504: The beta-barrel Exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing . The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. In RNA splicing, introns are removed and exons are covalently joined to one another as part of generating
782-518: The detergent . For example, the "unfolded" bacteriorhodopsin in SDS micelles has four transmembrane α-helices folded, while the rest of the protein is situated at the micelle-water interface and can adopt different types of non-native amphiphilic structures. Free energy differences between such detergent-denatured and native states are similar to stabilities of water-soluble proteins (< 10 kcal/mol). Refolding of α-helical transmembrane proteins in vitro
828-468: The molten globule states, formation of non-native disulfide bonds , or unfolding of peripheral regions and nonregular loops that are locally less stable. It is also important to properly define the unfolded state . The unfolded state of membrane proteins in detergent micelles is different from that in the thermal denaturation experiments. This state represents a combination of folded hydrophobic α-helices and partially unfolded segments covered by
874-510: The position of the protein N- and C-termini on the different sides of the lipid bilayer . Types I, II, III and IV are single-pass molecules . Type I transmembrane proteins are anchored to the lipid membrane with a stop-transfer anchor sequence and have their N-terminal domains targeted to the endoplasmic reticulum (ER) lumen during synthesis (and the extracellular space, if mature forms are located on cell membranes ). Type II and III are anchored with
920-400: 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
966-572: The GJB1 gene, and it is the only known gene to be associated with this disease. 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. 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. The GJB1 gene
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#17329083392951012-626: The GJB1 protein forms channels between cells as well as through myelin to the internal Schwann cell or oligodendrocyte, allowing effective transportation and communication. 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
1058-498: 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. Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate
1104-584: The exon that is contained in the insertional DNA . This new exon contains the ORF for a reporter gene that can now be expressed using the enhancers that control the target gene. A scientist knows that a new gene has been trapped when the reporter gene is expressed. Splicing can be experimentally modified so that targeted exons are excluded from mature mRNA transcripts by blocking the access of splice-directing small nuclear ribonucleoprotein particles (snRNPs) to pre-mRNA using Morpholino antisense oligos . This has become
1150-456: The exons include both the protein-coding sequence and the 5′- and 3′- untranslated regions (UTR). Often the first exon includes both the 5′-UTR and the first part of the coding sequence, but exons containing only regions of 5′-UTR or (more rarely) 3′-UTR occur in some genes, i.e. the UTRs may contain introns. Some non-coding RNA transcripts also have exons and introns. Mature mRNAs originating from
1196-455: The gene. 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. Surgical treatment most commonly includes osteotomies , soft-tissue surgery (including tendon transfers ) and/or joint fusions. Due to
1242-686: The inner membranes of bacterial cells or the plasma membrane of eukaryotic cells, and sometimes in the bacterial outer membrane . This is the major category of transmembrane proteins. In humans, 27% of all proteins have been estimated to be alpha-helical membrane proteins. Beta-barrel proteins are so far found only in outer membranes of gram-negative bacteria , cell walls of gram-positive bacteria , outer membranes of mitochondria and chloroplasts , or can be secreted as pore-forming toxins . All beta-barrel transmembrane proteins have simplest up-and-down topology, which may reflect their common evolutionary origin and similar folding mechanism. In addition to
1288-587: The mature RNA . Just as the entire set of genes for a species constitutes the genome , the entire set of exons constitutes the exome . The term exon derives from the expressed region and was coined by American biochemist Walter Gilbert in 1978: "The notion of the cistron ... must be replaced by that of a transcription unit containing regions which will be lost from the mature messenger – which I suggest we call introns (for intragenic regions) – alternating with regions which will be expressed – exons." This definition
1334-412: The membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them ( beta-barrels ) can be also extracted using denaturing agents . The peptide sequence that spans the membrane, or the transmembrane segment , is largely hydrophobic and can be visualized using the hydropathy plot . Depending on
1380-417: The mutated GJB1 gene and the differences in severity between heterozygous women and hemizygous men, with the later being more severely affected. 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. Some of these mutations also cause hearing loss in patients with CMTX. Currently it
1426-527: 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. The disease process involves demyelination of nerves due to impact on the Schwann cells , causing delayed transmission rates of nerve communication in
GJB1 - Misplaced Pages Continue
1472-492: 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. 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. Results from genetic testing can then be used to prevent
1518-438: The number of transmembrane segments, transmembrane proteins can be classified as single-pass membrane proteins , or as multipass membrane proteins. Some other integral membrane proteins are called monotopic , meaning that they are also permanently attached to the membrane, but do not pass through it. There are two basic types of transmembrane proteins: alpha-helical and beta barrels . Alpha-helical proteins are present in
1564-402: The peripheral nervous system some cases have been reported in which there is evidence of demyelination of the central nervous system . 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. Historically CMTX could only be diagnosed through symptoms or measurement of
1610-513: 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. Unlike many other types of CMT, CMT1X
1656-462: The positive inside rule and other methods have been developed. Transmembrane alpha-helical (α-helical) proteins are unusually stable judging from thermal denaturation studies, because they do not unfold completely within the membranes (the complete unfolding would require breaking down too many α-helical H-bonds in the nonpolar media). On the other hand, these proteins easily misfold , due to non-native aggregation in membranes, transition to
1702-463: The protein domains, there are unusual transmembrane elements formed by peptides. A typical example is gramicidin A , a peptide that forms a dimeric transmembrane β-helix. This peptide is secreted by gram-positive bacteria as an antibiotic . A transmembrane polyproline-II helix has not been reported in natural proteins. Nonetheless, this structure was experimentally observed in specifically designed artificial peptides. This classification refers to
1748-690: The protein has to be passed through the ER membrane in a direction dependent on the type. Membrane protein structures can be determined by X-ray crystallography , electron microscopy or NMR spectroscopy . The most common tertiary structures of these proteins are transmembrane helix bundle and beta barrel . The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell ) consist mostly of hydrophobic amino acids. Membrane proteins which have hydrophobic surfaces, are relatively flexible and are expressed at relatively low levels. This creates difficulties in obtaining enough protein and then growing crystals. Hence, despite
1794-428: The same gene need not include the same exons, since different introns in the pre-mRNA can be removed by the process of alternative splicing . Exonization is the creation of a new exon, as a result of mutations in introns . Exon trapping or ' gene trapping ' is a molecular biology technique that exploits the existence of the intron-exon splicing to find new genes. The first exon of a 'trapped' gene splices into
1840-432: The significant functional importance of membrane proteins, determining atomic resolution structures for these proteins is more difficult than globular proteins. As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20–30% of the total proteome. Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots,
1886-424: 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. 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
GJB1 - Misplaced Pages Continue
1932-574: The transfer of ions and small molecules between cells. For a general discussion of connexin proteins, see GJB2 . In Schwann cells, GJB1 also forms channels that facilitate transfers between layers of the myelin. In melanocytic cells GJB1 gene expression may be regulated by MITF . 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. Approximately four hundred type X Charcot-Marie-Tooth causing mutations have been identified within
1978-443: The translocon (although it would be at the membrane surface or unfolded in vitro ), because its polar residues can face the central water-filled channel of the translocon. Such mechanism is necessary for incorporation of polar α-helices into structures of transmembrane proteins. The amphiphilic helices remain attached to the translocon until the protein is completely synthesized and folded. If the protein remains unfolded and attached to
2024-461: The translocon for too long, it is degraded by specific "quality control" cellular systems. Stability of beta barrel (β-barrel) transmembrane proteins is similar to stability of water-soluble proteins, based on chemical denaturation studies. Some of them are very stable even in chaotropic agents and high temperature. Their folding in vivo is facilitated by water-soluble chaperones , such as protein Skp. It
2070-409: The transmission of this disease to their offspring. Transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane . Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through
2116-462: Was originally made for protein-coding transcripts that are spliced before being translated. The term later came to include sequences removed from rRNA and tRNA , and other ncRNA and it also was used later for RNA molecules originating from different parts of the genome that are then ligated by trans-splicing. Although unicellular eukaryotes such as yeast have either no introns or very few, metazoans and especially vertebrate genomes have
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