Peripheral myelin protein 22 (PMP22), also called Growth arrest-specific protein 3 (GAS-3), is a protein which in humans is encoded by the PMP22gene. Mutations in PMP22 cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies.
In humans, the PMP22 gene is located on chromosome 17p12 and spans approximately 40kb. The gene contains six exons conserved in both humans and rodents, two of which are 5’ untranslated exons (1a and 1b) and result in two different RNA transcripts with identical coding sequences. The two transcripts differ in their 5' untranslated regions and have their own promoter regulating expression. Exon 1a corresponds to protein transcription in the peripheral myelin sheath, while exon 1b corresponds to tissue outside of the nervous system.[8] The remaining exons (2 to 5) include the coding region of the PMP22 gene, and are joined together after post-transcriptional modification (i.e. alternative splicing).[6] The PMP22 protein is characterized by four transmembrane domains, two extracellular loops (ECL1 and ECL2), and one intracellular loop.[9] Exon 2 codes for the first transmembrane domain, located on the N-terminus of the PMP22 protein. Exon 3 codes for the first extracellular loop. Exon 4 corresponds to the second transmembrane domain and half of the third. Exon 5 is responsible for the rest of the third and the fourth transmembrane domain, the second extracellular loop, and the 3' UTR.[8] ECL1 has been suggested to mediate a homophilic interaction between two PMP22 proteins, whereas ECL2 has been shown to mediate a heterophilic interaction between PMP22 protein and Myelin protein zero (MPZ).[6]
Although the PMP22 mechanism of action in myelinating Schwann cells is not fully known, it plays an essential role in the formation and maintenance of compact myelin.[5] When Schwann cells come into contact with a neuronal axon, expression of PMP22 is significantly up-regulated,[6] whereas PMP22 is down-regulated during axonal degeneration or transection.[5] PMP22 has shown association with zonula-occludens 1 and occludin, proteins that are involved in adhesion with other cells and the extracellular matrix, and also support functioning of myelin.[5] Along with cell adhesion function, PMP22 is also up-regulated during Schwann cell proliferation, suggesting a role in cell-cycle regulation. PMP22 is detectable in non-neural tissues, where its expression has been shown to serve as growth-arrest-specific (gas-3) function.[5]
Gene-dosageedit
Improper gene dosage of the PMP22 gene can cause aberrant protein synthesis and function of myelin sheath. Since the components of myelin are stoichiometrically set, any irregular expression of a component can cause destabilization of myelin and neuropathic disorders.[5] Alterations of PMP22 gene expression are associated with a variety of neuropathies, such as Charcot–Marie–Tooth type 1A (CMT1A), Dejerine–Sottas disease, Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), and Charcot-Marie-Tooth type 1E (CMT1E).[6] Too much PMP22 (e.g. caused by gene duplication) results in CMT1A, and too little PMP22 (e.g. caused by gene deletion) results in HNPP.[10] Point mutations in PMP22 can result in CMT1E.[6] Gene duplication of PMP22 is the most common genetic cause of CMT;[11][12] up to half of all cases confirmed by a genetic diagnosis are caused by a 1.4 Mb duplication on chromosome 17, which contains the PMP22 gene.[13] Overproduction of PMP22 results in defects in multiple signaling pathways and dysfunction of transcriptional factors like KNOX20, SOX10 and EGR2.[5]
Interactions and Regulationedit
PMP22 has been found to interact with several different factors, some of which regulate expression. Peripheral myelin protein 22 has been shown to interact with myelin protein zero, with the proteins forming complexes in myelin.[14] Transcription factors SOX10 and EGR2 have been found to increase the expression of PMP22 through a super-enhancer upstream of the gene.[13]TEAD1 and YAP/TAZ (of the hippo signaling pathway) have been found to bind at the enhancers, with studies showing a decrease in PMP22 expression with the knockdown of these factors. Additionally, PKC activators and HDAC inhibitors have been characterized as regulators of PMP22, as well as microRNAs such as miR-29a and miR-381.[13]
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000109099 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000018217 - 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.
^ abcdefghWatila MM, Balarabe SA (August 2015). "Molecular and clinical features of inherited neuropathies due to PMP22 duplication". Journal of the Neurological Sciences. 355 (1–2): 18–24. doi:10.1016/j.jns.2015.05.037. PMID 26076881. S2CID 40080925.
^ abcdefLi J, Parker B, Martyn C, Natarajan C, Guo J (April 2013). "The PMP22 gene and its related diseases". Molecular Neurobiology. 47 (2): 673–698. doi:10.1007/s12035-012-8370-x. PMC3594637. PMID 23224996.
^Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, et al. (July 2002). "Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases". Proceedings of the National Academy of Sciences of the United States of America. 99 (15): 9852–9857. Bibcode:2002PNAS...99.9852D. doi:10.1073/pnas.152621799. PMC125041. PMID 12119418.
^ abZhang N, Zhu HP, Huang W, Wen X, Xie X, Jiang X, et al. (October 2022). "Unraveling the structures, functions and mechanisms of epithelial membrane protein family in human cancers". Experimental Hematology & Oncology. 11 (1): 69. doi:10.1186/s40164-022-00321-x. PMC9552464. PMID 36217151.
^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. doi:10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A. PMID 9888385. S2CID 31130790.
^Brennan KM, Bai Y, Shy ME (June 2015). "Demyelinating CMT--what's known, what's new and what's in store?". Neuroscience Letters. 596: 14–26. doi:10.1016/j.neulet.2015.01.059. PMID 25625223. S2CID 23911870.
^Al-Thihli K, Rudkin T, Carson N, Poulin C, Melançon S, Der Kaloustian VM (September 2008). "Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype". American Journal of Medical Genetics. Part A. 146A (18): 2412–2416. doi:10.1002/ajmg.a.32456. PMID 18698610. S2CID 205309846.
^Berger P, Young P, Suter U (March 2002). "Molecular cell biology of Charcot-Marie-Tooth disease". Neurogenetics. 4 (1): 1–15. doi:10.1007/s10048-002-0130-z. PMID 12030326. S2CID 25129077.
^D'Urso D, Ehrhardt P, Müller HW (May 1999). "Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin". The Journal of Neuroscience. 19 (9). Society for Neuroscience: 3396–3403. doi:10.1523/JNEUROSCI.19-09-03396.1999. PMC6782240. PMID 10212299.
Further readingedit
Patel PI, Lupski JR (April 1994). "Charcot-Marie-Tooth disease: a new paradigm for the mechanism of inherited disease". Trends in Genetics. 10 (4): 128–133. doi:10.1016/0168-9525(94)90214-3. PMID 7518101.
Roa BB, Lupski JR (1994). "Molecular Genetics of Charcot-Marie-Tooth Neuropathy". Advances in Human Genetics. Vol. 22. pp. 117–52. doi:10.1007/978-1-4757-9062-7_3. ISBN978-1-4757-9064-1. PMID 7762451.
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. doi:10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A. PMID 9888385. S2CID 31130790.
Jetten AM, Suter U (2000). "The peripheral myelin protein 22 and epithelial membrane protein family". Progress in Nucleic Acid Research and Molecular Biology. 64: 97–129. doi:10.1016/S0079-6603(00)64003-5. ISBN9780125400640. PMID 10697408.
External linksedit
GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1
April 10, 2024
peripheral, myelin, protein, pmp22, also, called, growth, arrest, specific, protein, protein, which, humans, encoded, pmp22, gene, mutations, pmp22, cause, changes, expression, peripheral, myelin, protein, which, result, several, neuropathies, pmp22identifiers. Peripheral myelin protein 22 PMP22 also called Growth arrest specific protein 3 GAS 3 is a protein which in humans is encoded by the PMP22 gene Mutations in PMP22 cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies PMP22IdentifiersAliasesPMP22 CMT1A CMT1E DSS GAS 3 HMSNIA HNPP Sujojp110 GAS3 peripheral myelin protein 22 CIDP Sp110External IDsOMIM 601097 MGI 97631 HomoloGene 7482 GeneCards PMP22Gene location Human Chr Chromosome 17 human 1 Band17p12Start15 229 773 bp 1 End15 272 292 bp 1 Gene location Mouse Chr Chromosome 11 mouse 2 Band11 B3 11 38 99 cMStart63 019 808 bp 2 End63 050 373 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inolfactory bulbtrigeminal ganglionspinal gangliatibial nervesynovial jointoptic nerveAchilles tendoninferior olivary nucleusmiddle frontal gyrusinferior ganglion of vagus nerveTop expressed insciatic nerveutricleankleright lung lobeankle jointanterior horn of spinal cordleft coloncarotid bodyfacial motor nucleusleft lungMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionprotein bindingCellular componentintegral component of membrane compact myelin plasma membrane membrane bicellular tight junctionBiological processmyelination cell differentiation bleb assembly cell death negative regulation of neuron projection development peripheral nervous system development negative regulation of cell population proliferation chemical synaptic transmission myelin assemblySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez537618858EnsemblENSG00000109099ENSMUSG00000018217UniProtQ01453P16646RefSeq mRNA NM 000304NM 001281455NM 001281456NM 153321NM 153322NM 001330143NM 001302255NM 001302257NM 001302258NM 001302259NM 001302260NM 001302261NM 008885RefSeq protein NP 000295NP 001268384NP 001268385NP 001317072NP 696996NP 696997NP 001289184NP 001289186NP 001289187NP 001289188NP 001289189NP 001289190NP 032911NP 001391071NP 001391072NP 001391206NP 001391207NP 001391208NP 001391209NP 001391210NP 001391211NP 001391212NP 001391213NP 001391214NP 001391215NP 001391216NP 001391217NP 001391218NP 001391219Location UCSC Chr 17 15 23 15 27 MbChr 11 63 02 63 05 MbPubMed search 3 4 WikidataView Edit HumanView Edit MousePMP22 is a 22 kDa transmembrane glycoprotein made up of 160 amino acids and is mainly expressed in the Schwann cells of the peripheral nervous system Schwann cells show high expression of PMP22 where it can constitute 2 5 of total protein content in compact myelin Compact myelin is the bulk of the peripheral neuron s myelin sheath a protective fatty layer that provides electrical insulation for the neuronal axon 5 The level of PMP22 expression is relatively low in the central nervous system of adults 6 Like other membrane proteins newly translated PMP22 protein is temporarily sequestered to the endoplasmic reticulum ER and Golgi apparatus for post translational modifications PMP22 protein is glycosylated with an N terminus linked sugar and co localized with the chaperone protein calnexin in the ER 7 After the protein is transported to the Golgi apparatus it can then become incorporated in the plasma membrane of the cell 5 Contents 1 Structure and function 2 Gene dosage 3 Interactions and Regulation 4 References 5 Further reading 6 External linksStructure and function editIn humans the PMP22 gene is located on chromosome 17p12 and spans approximately 40kb The gene contains six exons conserved in both humans and rodents two of which are 5 untranslated exons 1a and 1b and result in two different RNA transcripts with identical coding sequences The two transcripts differ in their 5 untranslated regions and have their own promoter regulating expression Exon 1a corresponds to protein transcription in the peripheral myelin sheath while exon 1b corresponds to tissue outside of the nervous system 8 The remaining exons 2 to 5 include the coding region of the PMP22 gene and are joined together after post transcriptional modification i e alternative splicing 6 The PMP22 protein is characterized by four transmembrane domains two extracellular loops ECL1 and ECL2 and one intracellular loop 9 Exon 2 codes for the first transmembrane domain located on the N terminus of the PMP22 protein Exon 3 codes for the first extracellular loop Exon 4 corresponds to the second transmembrane domain and half of the third Exon 5 is responsible for the rest of the third and the fourth transmembrane domain the second extracellular loop and the 3 UTR 8 ECL1 has been suggested to mediate a homophilic interaction between two PMP22 proteins whereas ECL2 has been shown to mediate a heterophilic interaction between PMP22 protein and Myelin protein zero MPZ 6 Although the PMP22 mechanism of action in myelinating Schwann cells is not fully known it plays an essential role in the formation and maintenance of compact myelin 5 When Schwann cells come into contact with a neuronal axon expression of PMP22 is significantly up regulated 6 whereas PMP22 is down regulated during axonal degeneration or transection 5 PMP22 has shown association with zonula occludens 1 and occludin proteins that are involved in adhesion with other cells and the extracellular matrix and also support functioning of myelin 5 Along with cell adhesion function PMP22 is also up regulated during Schwann cell proliferation suggesting a role in cell cycle regulation PMP22 is detectable in non neural tissues where its expression has been shown to serve as growth arrest specific gas 3 function 5 Gene dosage editImproper gene dosage of the PMP22 gene can cause aberrant protein synthesis and function of myelin sheath Since the components of myelin are stoichiometrically set any irregular expression of a component can cause destabilization of myelin and neuropathic disorders 5 Alterations of PMP22 gene expression are associated with a variety of neuropathies such as Charcot Marie Tooth type 1A CMT1A Dejerine Sottas disease Hereditary Neuropathy with Liability to Pressure Palsy HNPP and Charcot Marie Tooth type 1E CMT1E 6 Too much PMP22 e g caused by gene duplication results in CMT1A and too little PMP22 e g caused by gene deletion results in HNPP 10 Point mutations in PMP22 can result in CMT1E 6 Gene duplication of PMP22 is the most common genetic cause of CMT 11 12 up to half of all cases confirmed by a genetic diagnosis are caused by a 1 4 Mb duplication on chromosome 17 which contains the PMP22 gene 13 Overproduction of PMP22 results in defects in multiple signaling pathways and dysfunction of transcriptional factors like KNOX20 SOX10 and EGR2 5 Interactions and Regulation editPMP22 has been found to interact with several different factors some of which regulate expression Peripheral myelin protein 22 has been shown to interact with myelin protein zero with the proteins forming complexes in myelin 14 Transcription factors SOX10 and EGR2 have been found to increase the expression of PMP22 through a super enhancer upstream of the gene 13 TEAD1 and YAP TAZ of the hippo signaling pathway have been found to bind at the enhancers with studies showing a decrease in PMP22 expression with the knockdown of these factors Additionally PKC activators and HDAC inhibitors have been characterized as regulators of PMP22 as well as microRNAs such as miR 29a and miR 381 13 References edit a b c GRCh38 Ensembl release 89 ENSG00000109099 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000018217 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 a b c d e f g h Watila MM Balarabe SA August 2015 Molecular and clinical features of inherited neuropathies due to PMP22 duplication Journal of the Neurological Sciences 355 1 2 18 24 doi 10 1016 j jns 2015 05 037 PMID 26076881 S2CID 40080925 a b c d e f Li J Parker B Martyn C Natarajan C Guo J April 2013 The PMP22 gene and its related diseases Molecular Neurobiology 47 2 673 698 doi 10 1007 s12035 012 8370 x PMC 3594637 PMID 23224996 Dickson KM Bergeron JJ Shames I Colby J Nguyen DT Chevet E et al July 2002 Association of calnexin with mutant peripheral myelin protein 22 ex vivo a basis for gain of function ER diseases Proceedings of the National Academy of Sciences of the United States of America 99 15 9852 9857 Bibcode 2002PNAS 99 9852D doi 10 1073 pnas 152621799 PMC 125041 PMID 12119418 a b Zhang N Zhu HP Huang W Wen X Xie X Jiang X et al October 2022 Unraveling the structures functions and mechanisms of epithelial membrane protein family in human cancers Experimental Hematology amp Oncology 11 1 69 doi 10 1186 s40164 022 00321 x PMC 9552464 PMID 36217151 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 doi 10 1002 SICI 1098 1004 1999 13 1 lt 11 AID HUMU2 gt 3 0 CO 2 A PMID 9888385 S2CID 31130790 Brennan KM Bai Y Shy ME June 2015 Demyelinating CMT what s known what s new and what s in store Neuroscience Letters 596 14 26 doi 10 1016 j neulet 2015 01 059 PMID 25625223 S2CID 23911870 Al Thihli K Rudkin T Carson N Poulin C Melancon S Der Kaloustian VM September 2008 Compound heterozygous deletions of PMP22 causing severe Charcot Marie Tooth disease of the Dejerine Sottas disease phenotype American Journal of Medical Genetics Part A 146A 18 2412 2416 doi 10 1002 ajmg a 32456 PMID 18698610 S2CID 205309846 Berger P Young P Suter U March 2002 Molecular cell biology of Charcot Marie Tooth disease Neurogenetics 4 1 1 15 doi 10 1007 s10048 002 0130 z PMID 12030326 S2CID 25129077 a b c Pantera H Shy ME Svaren J January 2020 Regulating PMP22 expression as a dosage sensitive neuropathy gene Brain Research 1726 146491 doi 10 1016 j brainres 2019 146491 PMC 7006452 PMID 31586623 D Urso D Ehrhardt P Muller HW May 1999 Peripheral myelin protein 22 and protein zero a novel association in peripheral nervous system myelin The Journal of Neuroscience 19 9 Society for Neuroscience 3396 3403 doi 10 1523 JNEUROSCI 19 09 03396 1999 PMC 6782240 PMID 10212299 Further reading editPatel PI Lupski JR April 1994 Charcot Marie Tooth disease a new paradigm for the mechanism of inherited disease Trends in Genetics 10 4 128 133 doi 10 1016 0168 9525 94 90214 3 PMID 7518101 Roa BB Lupski JR 1994 Molecular Genetics of Charcot Marie Tooth Neuropathy Advances in Human Genetics Vol 22 pp 117 52 doi 10 1007 978 1 4757 9062 7 3 ISBN 978 1 4757 9064 1 PMID 7762451 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 doi 10 1002 SICI 1098 1004 1999 13 1 lt 11 AID HUMU2 gt 3 0 CO 2 A PMID 9888385 S2CID 31130790 Jetten AM Suter U 2000 The peripheral myelin protein 22 and epithelial membrane protein family Progress in Nucleic Acid Research and Molecular Biology 64 97 129 doi 10 1016 S0079 6603 00 64003 5 ISBN 9780125400640 PMID 10697408 External links editGeneReviews NCBI NIH UW entry on Charcot Marie Tooth Neuropathy Type 1 Retrieved from https en wikipedia org w index php title Peripheral myelin protein 22 amp oldid 1189079065, wikipedia, wiki, book, books, library,
