title: Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease.
abstract: Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by proteolipid protein 1 (PLP1) gene mutations. Previous studies indicated that proteolipid proteins (PLPs) with disease-associated mutations are misfolded and trapped in the endoplasmic reticulum (ER) during transportation to the cell surface, which eventually leads to oligodendrocyte cell death in PMD. Here we report a PMD patient with a very mild phenotype carrying a novel mutation (485G-->T) in exon 4 of the PLP1 gene that causes a Trp(162)Leu substitution in the protein. We also investigated intracellular trafficking of this mutant PLP in COS-7 cells. Transiently transfected mutant PLP(W162L) fused to an enhanced green fluorescent protein (EGFP) or a short peptide tag was not carried to the plasma membrane. However, in contrast to previous studies, this mutant PLP was not retained in the ER, indicating an escape of the newly translated protein from the quality control machinery. We also found that the mutant PLP accumulated in the nuclear envelope (NE) in a time-dependent manner. This mutant PLP, with its distribution outside the ER and a very mild phenotype, supports the idea that accumulation of misfolded mutant protein in the ER causes the severe phenotype of PMD.
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Koizume
authors.forename: S
authors.initials: S
authors.lastname: Takizawa
authors.forename: K
authors.initials: K
authors.lastname: Fujita
authors.forename: N
authors.initials: N
authors.lastname: Aida
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
authors.forename: H
authors.initials: H
authors.lastname: Osaka
mesh_terms: D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular / Q000379:methods; D005091:Exons; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D018000:Receptors, Peptide / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014364:Tryptophan / Q000235:genetics
chemical_list: C489304:KDELR1 protein, human; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D018000:Receptors, Peptide; D049452:Green Fluorescent Proteins; D014364:Tryptophan; D007930:Leucine