Peripheral myelin protein 22

Last updated
PMP22
Identifiers
Aliases PMP22 , CMT1A, CMT1E, DSS, GAS-3, HMSNIA, HNPP, Sujojp110, GAS3, peripheral myelin protein 22, CIDP, Sp110
External IDs OMIM: 601097 MGI: 97631 HomoloGene: 7482 GeneCards: PMP22
Orthologs
SpeciesHumanMouse
Entrez

5376

18858

Ensembl

ENSG00000109099

ENSMUSG00000018217

UniProt

Q01453

P16646

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr 17: 15.23 – 15.27 Mb Chr 11: 63.02 – 63.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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'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]

Structure and function

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-dosage

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 Regulation

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]

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">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">Calnexin</span> Mammalian protein found in Homo sapiens

Calnexin (CNX) is a 67kDa integral protein of the endoplasmic reticulum (ER). It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short, acidic cytoplasmic tail. In humans, calnexin is encoded by the gene CANX.

<span class="mw-page-title-main">Proteolipid protein 1</span> Type of myelin-associated protein

Proteolipid protein 1 (PLP1) is a form of myelin proteolipid protein (PLP). Mutations in PLP1 are associated with Pelizaeus–Merzbacher disease. It is a 4 transmembrane domain protein which is proposed to bind other copies of itself on the extracellular side of the membrane. In a myelin sheath, as the layers of myelin wraps come together, PLP will bind itself and tightly hold the cellular membranes together.

<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.

<span class="mw-page-title-main">MFN2</span> Protein-coding gene in the species Homo sapiens

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

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. 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.

<span class="mw-page-title-main">RAB7A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.

<span class="mw-page-title-main">EGR2</span> Protein-coding gene in the species Homo sapiens

Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 is a transcription regulatory factor, containing three zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development. When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects. These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.

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

Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.

<span class="mw-page-title-main">SURF1</span> Protein-coding gene in the species Homo sapiens

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex, which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).

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

Lipopolysaccharide-induced tumor necrosis factor-alpha factor is a protein that in humans is encoded by the LITAF 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">MTMR2</span> Protein-coding gene in the species Homo sapiens

Myotubularin-related protein 2 also known as phosphatidylinositol-3,5-bisphosphate 3-phosphatase or phosphatidylinositol-3-phosphate phosphatase is a protein that in humans is encoded by the MTMR2 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">SBF2</span> Protein-coding gene in the species Homo sapiens

Myotubularin-related protein 13 is a protein that in humans is encoded by the SBF2 gene.

<span class="mw-page-title-main">LRSAM1</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase LRSAM1, previously known as Tsg101-associated ligase (Tal), is an enzyme that in humans is encoded by the LRSAM1 gene.

<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.

<span class="mw-page-title-main">Fig4</span> Protein-coding gene in the species Homo sapiens

Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000109099 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018217 - 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 3 4 5 6 7 8 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.
  6. 1 2 3 4 5 6 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.
  7. ↑ 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.
  8. 1 2 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 & Oncology. 11 (1): 69. doi: 10.1186/s40164-022-00321-x . PMC   9552464 . PMID   36217151.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. 1 2 3 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.
  14. ↑ 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. Society for Neuroscience. 19 (9): 3396–3403. doi: 10.1523/JNEUROSCI.19-09-03396.1999 . PMC   6782240 . PMID   10212299.

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