title: Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.
abstract: Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.
authors.affiliation: Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.forename: P
authors.initials: P
authors.lastname: Montague
authors.forename: I
authors.initials: I
authors.lastname: Griffiths
authors.forename: M
authors.initials: M
authors.lastname: Fanarraga
authors.forename: P
authors.initials: P
authors.lastname: Kennedy
authors.forename: P
authors.initials: P
authors.lastname: Brophy
authors.forename: K A
authors.initials: KA
authors.lastname: Nave
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000033:anatomy & histology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009457:Neuroglia / Q000473:pathology*; D013329:Structure-Activity Relationship
chemical_list: D008565:Membrane Proteins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein