title: Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications.
abstract: Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10-25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.
authors.affiliation: International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ward, Tokyo 162-8666, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimojima
authors.forename: Takehiko
authors.initials: T
authors.lastname: Inoue
authors.forename: Ai
authors.initials: A
authors.lastname: Hoshino
authors.forename: Satsuki
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Nishimura
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeshita-Yanagisawa
authors.forename: Go
authors.initials: G
authors.lastname: Tajima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozawa
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saito
authors.forename: Makiko
authors.initials: M
authors.lastname: Osawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto