title: Tissue-specific splicing mutation in acute intermittent porphyria.
abstract: An inherited deficiency of porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in humans is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. It was previously demonstrated that porphobilinogen deaminase is encoded by two distinct mRNA species expressed in a tissue-specific manner. Analysis of the genomic sequences indicated that these two mRNAs are transcribed from two promoters and only differ in their first exon. The first mutation identified in the human porphobilinogen deaminase gene is a single-base substitution (G----A) in the canonical 5' splice donor site of intron 1. This mutation leads to a particular subtype of acute intermittent porphyria characterized by the restriction of the enzymatic defect to nonerythropoietic tissues. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offers another possibility of detecting asymptomatic carriers of the mutation in affected families.
authors.affiliation: Laboratoire de Génétique Moléculaire, Faculté de Médecine X, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Grandchamp
authors.forename: C
authors.initials: C
authors.lastname: Picat
authors.forename: V
authors.initials: V
authors.lastname: Mignotte
authors.forename: J H
authors.initials: JH
authors.lastname: Wilson
authors.forename: K
authors.initials: K
authors.lastname: Te Velde
authors.forename: L
authors.initials: L
authors.lastname: Sandkuyl
authors.forename: P H
authors.initials: PH
authors.lastname: Roméo
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: Y
authors.initials: Y
authors.lastname: Nordmann
mesh_terms: D000208:Acute Disease; D000642:Ammonia-Lyases / Q000235:genetics*; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D015342:DNA Probes; D005260:Female; D005784:Gene Amplification; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D017118:Porphyria, Acute Intermittent; D011164:Porphyrias / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D015342:DNA Probes; D012333:RNA, Messenger; D004247:DNA; D011163:Hydroxymethylbilane Synthase; D000642:Ammonia-Lyases