title: DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences.
abstract: Until the identification of ABCA12 as the causative gene, prenatal diagnosis (PD) for harlequin ichthyosis (HI) had been performed by electron microscopic observation of fetal skin biopsy samples. We report the first case of HI DNA-based PD. Direct sequence analysis of ABCA12 revealed that the deceased proband was a compound heterozygote for two novel mutations. The maternal nonsense mutation p.Ser1249Term likely leads to nonsense-mediated messenger RNA decay. The paternal mutation c.7436G>A affects the last codon of exon 50 and was expected to be a splice site mutation. For their third pregnancy, the parents requested PD. Direct sequence analysis of fetal genomic DNA from amniotic fluid cells at 17 weeks gestation revealed the fetus was a compound heterozygote for both mutations. The parents requested the pregnancy to be terminated. Analysis of ABCA12 transcripts of cultured keratinocytes from the abortus showed the presence of six abnormally spliced products from the allele carrying the splice site mutation. Four of them lead to premature termination codons whereas the two others produced shortened proteins missing 21 and 31 amino acids from the second ATP-binding cassette. This report provides evidence for residual ABCA12 expression in HI, and demonstrates the efficiency of early DNA-based PD of HI.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. akiyama@med.hokudai.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Matthias
authors.initials: M
authors.lastname: Titeux
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakai
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.forename: Laure
authors.initials: L
authors.lastname: Tonasso
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.forename: Frederique
authors.initials: F
authors.lastname: Jossic
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000175:diagnosis* / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012689:Sequence Homology, Nucleic Acid
chemical_list: C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA