title: Mild phenotype in Pelizaeus-Merzbacher disease caused by a PLP1-specific mutation.
abstract: We present the case of a 26 year-old man who developed normally until he began having difficulty walking at age 12. He subsequently became unable to stand at 15 years old and exhibited mental regression and generalized tonic convulsions by age 20. Magnetic resonance imaging revealed incomplete myelination of cerebral white matter, which resembled that of Pelizaeus-Merzbacher disease. By sequencing the proteolipid protein 1 (PLP1) gene, we found a novel mutation (c.352_353delAG (p.Gly130fs)) in the latter half of exon 3 (exon 3B) that is spliced out in the DM20 isoform. Exon 3B mutations are known to cause a mild phenotype since they do not disturb DM20 production. Mutations that truncate PLP1 correlate with a mild phenotype by activating the nonsense-mediated decay mechanism that specifically detects and degrades mRNAs containing a premature termination codon. This attenuates the production of toxic mutant PLP1. The very mild presentation in the present case seems to be derived from the unique nature of the mutation, which preserves DM20 production and decreases mutant PLP1.
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama 232-855, Japan. hosaka@kcmc.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Shiro
authors.initials: S
authors.lastname: Koizume
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Aoyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Kimura
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000328:Adult; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human