title: Mutations of peripheral myelin protein 22 result in defective trafficking through mechanisms which may be common to diseases involving tetraspan membrane proteins.
abstract: Phenotypes of several heritable disorders including forms of hearing loss, myelin diseases, hypomagnesemia, and cataracts are linked to missense mutations in single alleles encoding membrane proteins having four transmembrane spans. In some cases, the mutant proteins exhibit dominant negative or gain-of-function behavior whereby heterozygous coexpression of mutant and wild-type genes leads to more serious pathology than is the case for individuals in which only a single wild-type allele is expressed. An example is found in the relationship of peripheral myelin protein 22 (PMP22) to Charcot-Marie-Tooth disease (CMTD) type 1A. A number of disease-linked PMP22 mutants fail to undergo normal trafficking beyond the endoplasmic reticulum or intermediate compartment to reach the cell surface. Moreover, recent evidence suggests that pathology resulting from this mistrafficking-based loss of function may also be augmented by the ability of some mutants to disrupt normal trafficking of the product of the wild-type PMP22 allele. The basis for this phenomenon appears to be the heterodimerization of trafficking-incompetent mutants with wild-type PMP22, such that both the wild-type protein and the mutant forms are retained early in the secretory pathway. The full cellular and structural biological details of these observations remain to be elucidated. However, the model suggested by the existing data regarding the relationship of PMP22 to CMTD may be useful to explain phenotypes of several other diseases involving other tetraspan membrane proteins and to facilitate predictions regarding previously undetected disease-protein linkages.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA. crs4@po.cwru.edu
authors.forename: C R
authors.initials: CR
authors.lastname: Sanders
authors.forename: F
authors.initials: F
authors.lastname: Ismail-Beigi
authors.forename: M W
authors.initials: MW
authors.lastname: McEnery
mesh_terms: D000595:Amino Acid Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology*; D016415:Sequence Alignment
chemical_list: D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; C073687:PMP22 protein, human