title: CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy.
abstract: Genetic and phenotypic heterogeneities are considerably high in adult-onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult-onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult-onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy-proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R as well as cross-species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies.
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.forename: Taro L
authors.initials: TL
authors.lastname: Saito
authors.forename: Budrul
authors.initials: B
authors.lastname: Ahsan
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Yuki
authors.initials: Y
authors.lastname: Niimi
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Riku
authors.forename: Yoji
authors.initials: Y
authors.lastname: Goto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mano
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor