Peripheral myelin protein 22

2018-07-20T02:00:44Z

2601:14F:8002:11E4:E127:1AB9:5B51:8BDC: All patients with CMT-1A have a PMP22 duplication, and about 40% of the patients with CMT are diagnosed with PMP22 duplication = are diagnosed with CMT-1A.

{{Infobox_gene}}

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

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 | year = 2015 | pmid = 26076881 | doi = 10.1016/j.jns.2015.05.037 }}</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 = 673–98 | year = 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 | title = Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for “gain-of-function” ER diseases | journal = PNAS USA | volume = 99 | issue = 15 | pages = 9852–857 | date = July 2002 | pmid = 12119418 | doi = 10.1073/pnas.152621799 | pmc=125041}}</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]]p11.2 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. 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 | url = }}</ref> 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]], and [[Hereditary neuropathy with liability to pressure palsy|Hereditary Neuropathy with Liability to Pressure Palsy]] (HNPP). 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 | issue = | pages = 14–26 | year = 2015 | pmid = 25625223 | doi = 10.1016/j.neulet.2015.01.059 }}</ref> 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 = 2412–6 | year = 2008 | pmid = 18698610 | doi = 10.1002/ajmg.a.32456 }}</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 | year = 2002 | pmid = 12030326 | doi = 10.1007/s10048-002-0130-z }}</ref> where the overproduction of PMP22 results in defects in multiple signalling pathways and dysfunction of [[transcription factor|transcriptional factors]] like KNOX20, [[SOX10]] and [[EGR2]].<ref name= "Watila" />

== Interactions ==

Peripheral myelin protein 22 has been shown to [[Protein–protein interaction|interact]] with [[myelin protein zero]].<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 = 3396–403 | date = May 1999 | pmid = 10212299 | url = http://www.jneurosci.org/content/19/9/3396.full.pdf | publisher = Society for Neuroscience }}</ref>

== 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 = 128–33 | date = Apr 1994 | pmid = 7518101 | doi = 10.1016/0168-9525(94)90214-3 }}
* {{cite journal | vauthors = Roa BB, Lupski JR | title = Molecular genetics of Charcot-Marie-Tooth neuropathy | journal = Advances in Human Genetics | volume = 22 | issue = | pages = 117–52 | year = 1995 | pmid = 7762451 | doi = 10.1007/978-1-4757-9062-7_3 }}
* {{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 }}
* {{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 | issue = | pages = 97–129 | year = 2000 | pmid = 10697408 | doi = 10.1016/S0079-6603(00)64003-5 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cmt1 GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1]

wikidoc - User contributions [en]

Peripheral myelin protein 22