{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}}
'''Peripheral myelin protein 22''' (PMP22), also called '''Growth arrest-specific protein 3''' (GAS-3), is a [[protein]] which in [[human]]s 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.
PMP22 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|neuron's]] [[myelin sheath]], a protective fatty layer that provides electrical insulation for the neuronal [[axon]].<ref name= "Watila">{{cite journal | vauthors = Watila MM, Balarabe SA | title = Molecular and clinical features of inherited neuropathies due to PMP22 duplication | journal = Journal of the Neurological Sciences | volume = 355 | issue = 1–2 | pages = 18–24 | date = August 2015 | pmid = 26076881 | doi = 10.1016/j.jns.2015.05.037 | s2cid = 40080925 }}</ref> The level of PMP22 expression is relatively low in the [[central nervous system]] of adults.<ref name= "Structure">{{cite journal | vauthors = Li J, Parker B, Martyn C, Natarajan C, Guo J | title = The PMP22 gene and its related diseases | journal = Molecular Neurobiology | volume = 47 | issue = 2 | pages = 673–698 | date = April 2013 | pmid = 23224996 | pmc = 3594637 | doi = 10.1007/s12035-012-8370-x }}</ref>
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 [[Glycosylation|glycosylated]] with an [[N-linked glycosylation|N terminus-linked]] sugar and co-localized with the [[chaperone protein]] [[calnexin]] in the ER.<ref name=pmid12119418>{{cite journal | vauthors = Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ | display-authors = 6 | title = Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 15 | pages = 9852–9857 | date = July 2002 | pmid = 12119418 | pmc = 125041 | doi = 10.1073/pnas.152621799 | doi-access = free | bibcode = 2002PNAS...99.9852D }}</ref> After the protein is transported to the Golgi apparatus it can then become incorporated in the [[plasma membrane]] of the cell.<ref name= "Watila" />
== Structure and function == In humans, the PMP22 gene is located on [[chromosome 17]]p12 and spans approximately 40kb. The gene contains six [[exons]] conserved in both humans and rodents, two of which are [[Five prime untranslated region|5' untranslated]] exons (1a and 1b) and result in two different [[RNA|RNA transcripts]] with identical [[coding region|coding sequences]]. The two transcripts differ in their 5' untranslated regions and have their own [[Promoter (genetics)|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.<ref name="Zhang_2022">{{cite journal | vauthors = Zhang N, Zhu HP, Huang W, Wen X, Xie X, Jiang X, Peng C, Han B, He G | display-authors = 6 | title = Unraveling the structures, functions and mechanisms of epithelial membrane protein family in human cancers | journal = Experimental Hematology & Oncology | volume = 11 | issue = 1 | page = 69 | date = October 2022 | pmid = 36217151 | pmc = 9552464 | doi = 10.1186/s40164-022-00321-x | doi-access = free }}</ref> 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]]).<ref name= "Structure"/> The PMP22 protein is characterized by four [[transmembrane domains]], two extracellular loops (ECL1 and ECL2), and one intracellular loop.<ref name= "Hello">{{cite journal | vauthors = Nelis E, Haites N, Van Broeckhoven C | title = Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies | journal = Human Mutation | volume = 13 | issue = 1 | pages = 11–28 | year = 1999 | pmid = 9888385 | doi = 10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A | s2cid = 31130790 | doi-access = free }}</ref> 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]].<ref name="Zhang_2022" /> 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).<ref name= "Structure"/>
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.<ref name= "Watila" /> When Schwann cells come into contact with a neuronal axon, expression of PMP22 is significantly [[Downregulation and upregulation|up-regulated]],<ref name= "Structure"/> whereas PMP22 is [[Downregulation and upregulation|down-regulated]] during axonal degeneration or transection.<ref name= "Watila" /> PMP22 has shown association with [[Tight junction protein 1|zonula-occludens 1]] and [[occludin]], proteins that are involved in adhesion with other cells and the extracellular matrix, and also support functioning of myelin.<ref name= "Watila" /> 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.<ref name= "Watila"/>
== Gene-dosage == Improper [[gene dosage]] of the PMP22 gene can cause aberrant protein synthesis and function of myelin sheath. Since the components of myelin are [[stoichiometry|stoichiometrically]] set, any irregular expression of a component can cause destabilization of myelin and neuropathic disorders.<ref name= "Watila"/> Alterations of PMP22 gene expression are associated with a variety of neuropathies, such as [[Charcot–Marie–Tooth disease|Charcot–Marie–Tooth type 1A]] (CMT1A), [[Dejerine–Sottas disease]], [[Hereditary neuropathy with liability to pressure palsy|Hereditary Neuropathy with Liability to Pressure Palsy]] (HNPP), and Charcot-Marie-Tooth type 1E (CMT1E).<ref name="Structure" /> 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.<ref name= " Brennan">{{cite journal | vauthors = Brennan KM, Bai Y, Shy ME | title = Demyelinating CMT--what's known, what's new and what's in store? | journal = Neuroscience Letters | volume = 596 | pages = 14–26 | date = June 2015 | pmid = 25625223 | doi = 10.1016/j.neulet.2015.01.059 | s2cid = 23911870 }}</ref> Point mutations in ''PMP22'' can result in CMT1E.<ref name="Structure" /> Gene duplication of PMP22 is the most common genetic cause of CMT;<ref name="CMT1A">{{cite journal | vauthors = Al-Thihli K, Rudkin T, Carson N, Poulin C, Melançon S, Der Kaloustian VM | title = Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 18 | pages = 2412–2416 | date = September 2008 | pmid = 18698610 | doi = 10.1002/ajmg.a.32456 | s2cid = 205309846 }}</ref><ref name="CMT1A2">{{cite journal | vauthors = Berger P, Young P, Suter U | title = Molecular cell biology of Charcot-Marie-Tooth disease | journal = Neurogenetics | volume = 4 | issue = 1 | pages = 1–15 | date = March 2002 | pmid = 12030326 | doi = 10.1007/s10048-002-0130-z | s2cid = 25129077 }}</ref> 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.<ref name="Pantera_2020">{{cite journal | vauthors = Pantera H, Shy ME, Svaren J | title = Regulating PMP22 expression as a dosage sensitive neuropathy gene | journal = Brain Research | volume = 1726 | issue = | article-number = 146491 | date = January 2020 | pmid = 31586623 | pmc = 7006452 | doi = 10.1016/j.brainres.2019.146491 }}</ref> Overproduction of PMP22 results in defects in multiple signaling pathways and dysfunction of [[transcription factor|transcriptional factors]] like KNOX20, [[SOX10]] and [[EGR2]].<ref name= "Watila" />
== Interactions and Regulation ==
''PMP22'' has been found to interact with several different factors, some of which regulate expression. Peripheral myelin protein 22 has been shown to [[Protein–protein interaction|interact]] with [[myelin protein zero]], with the proteins forming complexes in myelin.<ref name=pmid10212299>{{cite journal | vauthors = D'Urso D, Ehrhardt P, Müller HW | title = Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin | journal = The Journal of Neuroscience | volume = 19 | issue = 9 | pages = 3396–3403 | date = May 1999 | pmid = 10212299 | pmc = 6782240 | doi = 10.1523/JNEUROSCI.19-09-03396.1999 | publisher = Society for Neuroscience | doi-access = free }}</ref> Transcription factors [[SOX10]] and [[EGR2]] have been found to increase the expression of PMP22 through a [[super-enhancer]] upstream of the gene.<ref name="Pantera_2020" /> [[TEAD1]] and [[YAP1|YAP]]/[[WWTR1|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, [[Protein kinase C|PKC]] activators and [[Histone deacetylase inhibitor|HDAC inhibitors]] have been characterized as regulators of PMP22, as well as [[microRNA]]s such as [[mir-29 microRNA precursor|miR-29a]] and miR-381.<ref name="Pantera_2020" />
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Patel PI, Lupski JR | title = Charcot-Marie-Tooth disease: a new paradigm for the mechanism of inherited disease | journal = Trends in Genetics | volume = 10 | issue = 4 | pages = 128–133 | date = April 1994 | pmid = 7518101 | doi = 10.1016/0168-9525(94)90214-3 }} * {{cite book | vauthors = Roa BB, Lupski JR | title = Advances in Human Genetics | chapter = Molecular Genetics of Charcot-Marie-Tooth Neuropathy | date = 1994 | volume = 22 | pages = 117–52 | pmid = 7762451 | doi = 10.1007/978-1-4757-9062-7_3 | isbn = 978-1-4757-9064-1 }} * {{cite journal | vauthors = Nelis E, Haites N, Van Broeckhoven C | title = Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies | journal = Human Mutation | volume = 13 | issue = 1 | pages = 11–28 | year = 1999 | pmid = 9888385 | doi = 10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A | s2cid = 31130790 | doi-access = free }} * {{cite journal | vauthors = Jetten AM, Suter U | title = The peripheral myelin protein 22 and epithelial membrane protein family | journal = Progress in Nucleic Acid Research and Molecular Biology | volume = 64 | pages = 97–129 | year = 2000 | pmid = 10697408 | doi = 10.1016/S0079-6603(00)64003-5 | isbn = 978-0-12-540064-0 | url = https://zenodo.org/record/1259753 }} {{refend}}
== External links == * [https://www.ncbi.nlm.nih.gov/books/NBK1205/ GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1]