title: Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region.
abstract: Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked leukodystrophy presenting with motor developmental delay associated with spasticity and nystagmus. PMD is mainly caused by abnormalities in the proteolipid protein 1 gene (PLP1), most frequently due to duplications of chromosomal segments including PLP1. In this study, a 9-year-old male patient manifesting severe developmental delay and spasticity was analyzed for PLP1 alteration, and triplication of PLP1 was identified. Further examination revealed an underlying genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which a triplicated segment was nested between 2 junctions. One of the 2 junctions was caused by inverted homologous regions, and the other was caused by non-homologous end-joining. PMD patients with PLP1 duplications usually show milder-classical forms of the disease compared with patients with PLP1 missense mutations manifesting severe connatal forms. The present patient showed severe phenotypic features that represent an intermediate form of PMD between classical and connatal forms. This is the first report of a patient with PLP1 triplication caused by a DUP-TRP/INV-DUP structure. This study adds additional evidence about the consequences of PLP1 triplication.
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimojima
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mano
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kashiwagi
authors.forename: Takuya
authors.initials: T
authors.lastname: Tanabe
authors.forename: Midori
authors.initials: M
authors.lastname: Sugawara
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D001483:Base Sequence; D002648:Child; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X / Q000235:genetics; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000175:diagnosis* / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human