title: Mutational analysis of patients with X-linked adrenoleukodystrophy.
abstract: Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.
authors.affiliation: Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: F
authors.initials: F
authors.lastname: Kok
authors.forename: S
authors.initials: S
authors.lastname: Neumann
authors.forename: C O
authors.initials: CO
authors.lastname: Sarde
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.forename: K H
authors.initials: KH
authors.lastname: Wu
authors.forename: H M
authors.initials: HM
authors.lastname: Wei
authors.forename: J
authors.initials: J
authors.lastname: Bergin
authors.forename: P A
authors.initials: PA
authors.lastname: Watkins
authors.forename: S
authors.initials: S
authors.lastname: Gould
authors.forename: G
authors.initials: G
authors.lastname: Sack
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D008040:Genetic Linkage; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D014960:X Chromosome
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins