title: Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.
abstract: Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p=0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Muriel
authors.initials: M
authors.lastname: Asheuer
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimozawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takano
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics*; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005602:France; D005787:Gene Frequency; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; C063305:ABCD3 protein, human; C489273:ABCD4 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers