title: Mutational analyses on X-linked adrenoleukodystrophy reveal a novel cryptic splicing and three missense mutations in the ABCD1 gene.
abstract: BACKGROUND
  X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids.
  
  
  METHODS
  Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families.
  
  
  RESULTS
  A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121 bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands.
  
  
  CONCLUSIONS
  This is the first report to unveil unequivocally that cryptic splicing-induced aberrant messenger-RNA carrying an internal frameshift deletion results from an intronic mutation in the ABCD1 gene. Furthermore, a polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was commonly observed in both Taiwanese and Malaysian populations.
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan ROC.
authors.forename: Kun-Long
authors.initials: KL
authors.lastname: Hung
authors.forename: Jinn-Shyan
authors.initials: JS
authors.lastname: Wang
authors.forename: Wee Teik
authors.initials: WT
authors.lastname: Keng
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Jao-Shwann
authors.initials: JS
authors.lastname: Liang
authors.forename: Lock Hock
authors.initials: LH
authors.lastname: Ngu
authors.forename: Jyh-Feng
authors.initials: JF
authors.lastname: Lu
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008296:Malaysia; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009716:Numerical Analysis, Computer-Assisted; D017384:Sequence Deletion; D013624:Taiwan
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters