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Peripheral myelin protein 22 (PMP22), also called Growth arrest-specific protein 3 (GAS-3), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in
human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
s is encoded by the ''PMP22''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Mutations in ''PMP22'' cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies. PMP22 is a 22
kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
transmembrane 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 u ...
glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
made up of 160
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
, and is mainly expressed in the
Schwann cells Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...
of the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
. Schwann cells show high expression of PMP22, where it can constitute 2-5% of total protein content in compact
myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
. Compact myelin is the bulk of the peripheral neuron's
myelin sheath Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
, a protective fatty layer that provides electrical insulation for the neuronal
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
. The level of PMP22 expression is relatively low in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
of adults. Like other membrane proteins, newly translated PMP22 protein is temporarily sequestered to the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER) and
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
for post-translational modifications. PMP22 protein is
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
with an N terminus-linked sugar and co-localized with the
chaperone protein In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...
calnexin Calnexin (CNX) is a 67kDa integral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calciu ...
in the ER. After the protein is transported to the Golgi apparatus it can then become incorporated in the
plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
of the cell.


Structure and function

In humans, the PMP22 gene is located on
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
p12 and spans approximately 40kb. The gene contains six
exons 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 i ...
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. The remaining exons (2 to 5) include the coding region of the PMP22 gene, and are joined together after
post-transcriptional modification Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, f ...
(i.e.
alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
). The PMP22 protein is characterized by four
transmembrane domains A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...
, two extracellular loops (ECL1 and ECL2), and one intracellular loop. Exon 2 codes for the first transmembrane domain, located on the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
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 In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation (biology), translation termination codon. The 3′-UTR often contains regulatory regions that P ...
. 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 Myelin protein zero (MPZ), also Myelin protein P0, 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 ...
(MPZ). 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. When Schwann cells come into contact with a neuronal axon, expression of PMP22 is significantly up-regulated, whereas PMP22 is down-regulated during axonal degeneration or transection. PMP22 has shown association with zonula-occludens 1 and
occludin Occludin is a transmembrane protein that regulates the permeability of epithelial and endothelial barriers. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions. Together with ...
, proteins that are involved in adhesion with other cells and the extracellular matrix, and also support functioning of myelin. Along with cell adhesion function, PMP22 is also up-regulated during Schwann
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
, suggesting a role in
cell-cycle regulation The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA replication) and s ...
. PMP22 is detectable in non-neural tissues, where its expression has been shown to serve as growth-arrest-specific (gas-3) function.


Gene-dosage

Improper
gene dosage Gene dosage is the number of copies of a particular gene present in a genome. Gene dosage is related to the amount of gene product (proteins or functional RNAs) the cell is able to express. Since a gene acts as a template, the number of templates i ...
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. Alterations of PMP22 gene expression are associated with a variety of neuropathies, such as Charcot–Marie–Tooth type 1A (CMT1A),
Dejerine–Sottas disease Dejerine–Sottas disease, also known as, Dejerine–Sottas syndrome, hereditary motor and sensory polyneuropathy type III, and Charcot–Marie–Tooth disease type 3, is a hereditary neurological disorder characterized by damage to the peripheral ...
,
Hereditary Neuropathy with Liability to Pressure Palsy Hereditary neuropathy with liability to pressure palsy (HNPP) is a peripheral neuropathy, a condition that affects the nerves.update 2014 Pressure on the nerves can cause tingling sensations, numbness, pain, weakness, muscle atrophy and even paraly ...
(HNPP), and Charcot-Marie-Tooth type 1E (CMT1E). Too much PMP22 (e.g. caused by
gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...
) results in CMT1A, and too little PMP22 (e.g. caused by
gene deletion In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...
) results in HNPP. Point mutations in ''PMP22'' can result in CMT1E. Gene duplication of PMP22 is the most common genetic cause of CMT; 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. Overproduction of PMP22 results in defects in multiple signaling pathways and dysfunction of transcriptional factors like KNOX20,
SOX10 Transcription factor SOX-10 is a protein that in humans is encoded by the ''SOX10'' gene. Function This gene encodes a member of the SOX gene family, SOX (Testis-determining factor, SRY-related HMG-box) family of transcription factors involved ...
and
EGR2 Early growth response protein 2 is a protein that in humans is encoded by the ''EGR2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA t ...
.


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 Myelin protein zero (MPZ), also Myelin protein P0, 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 ...
, with the proteins forming complexes in myelin. Transcription factors
SOX10 Transcription factor SOX-10 is a protein that in humans is encoded by the ''SOX10'' gene. Function This gene encodes a member of the SOX gene family, SOX (Testis-determining factor, SRY-related HMG-box) family of transcription factors involved ...
and
EGR2 Early growth response protein 2 is a protein that in humans is encoded by the ''EGR2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA t ...
have been found to increase the expression of PMP22 through a
super-enhancer Cell differentiation in multicellular organism A multicellular organism is an organism that consists of more than one cell (biology), cell, unlike unicellular organisms. All species of animals, Embryophyte, land plants and most fungi are multi ...
upstream of the gene. TEAD1 and
YAP Yap (, sometimes written as , or ) traditionally refers to an island group located in the Caroline Islands of the western Pacific Ocean, a part of Yap State. The name "Yap" in recent years has come to also refer to the state within the Federate ...
/
TAZ Taz or TAZ may refer to: Geography *Taz (river), a river in western Siberia, Russia *Taz Estuary, the estuary of the river Taz in Russia People * Taz people, an ethnic group in Russia ** Taz language, a form of Northeastern Mandarin spoken by ...
(of the
hippo signaling pathway The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of it ...
) 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 Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcrip ...
have been characterized as regulators of PMP22, as well as
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
s such as miR-29a and miR-381.


References


Further reading

* * * * {{refend


External links


GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1