title: X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients.
abstract: X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females.
authors.affiliation: Centro de Estudio de las Metabolopatías Congénitas-CEMECO, Cátedra de Clínica Pediátrica, Facultad de Medicina, Universidad Nacional de Córdoba, Hospital de Niños, Córdoba, Argentina. cytiam@hotmail.com
authors.forename: Cyntia Anabel
authors.initials: CA
authors.lastname: Amorosi
authors.forename: Helena
authors.initials: H
authors.lastname: Myskóva
authors.forename: Mariela Roxana
authors.initials: MR
authors.lastname: Monti
authors.forename: Carlos Enrique
authors.initials: CE
authors.lastname: Argaraña
authors.forename: Masashi
authors.initials: M
authors.lastname: Morita
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Raquel
authors.initials: R
authors.lastname: Dodelson de Kremer
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvoráková
authors.forename: Ana María
authors.initials: AM
authors.lastname: Oller de Ramírez
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics*; D000595:Amino Acid Sequence; D001118:Argentina; D001483:Base Sequence; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D022821:RNA Splice Sites
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D022821:RNA Splice Sites