title: A splicing mutation in the hydroxymethylbilane synthase gene in a Japanese family with acute intermittent porphyria.
abstract: OBJECTIVE
  Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease caused by a decreased activity of hydroxymethylbilane synthase (HMBS). As far as the gene abnormalities of the HMBS, many different mutations have been reported. In this work, we investigated the presence of mutations in a Japanese family with AIP.
  
  
  METHODS
  A 44-year-old Japanese male and nine members of his family were investigated. All of them were screened by traditional biochemical markers. Mutational analysis was performed using polymerase chain reaction-single strand conformation polymorphism method followed by DNA sequencing. A reliable restriction enzyme cleavage assay was established for the pedigree analysis.
  
  
  RESULTS
  The mutation was a splicing mutation, a C to G transversion at position -3 of the acceptor site of intron 11 of the HMBS gene, resulting in the exon 12 skipping. The patient is heterozygous for the mutation, and his father appeared to be the source of the mutant allele. This mutation created a new cleavage site of the Nla III restriction enzyme and could be screened by a amplified fragment from genomic DNA with digestion. Using this cleavage assay, an asymptomatic carrier in the family was definitively identified.
  
  
  CONCLUSIONS
  This mutation was first found among Japanese AIP patients, but happened to be the same as reported previously from Europe. A similarity of gene abnormality may suggest that those European and Japanese AIP families have a common ancestor. Molecular investigations on the family members should be applied not only for more accurate diagnosis, but also for understanding the molecular genetic heterogeneity underlying this dominantly inherited enzymopathy.
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan. nmaeda@grape.med.tottori-u.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Maeda
authors.forename: Y
authors.initials: Y
authors.lastname: Horie
authors.forename: Y
authors.initials: Y
authors.lastname: Sasaki
authors.forename: E
authors.initials: E
authors.lastname: Ueta
authors.forename: K
authors.initials: K
authors.lastname: Adachi
authors.forename: E
authors.initials: E
authors.lastname: Nanba
authors.forename: H
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kudo
authors.forename: M
authors.initials: M
authors.lastname: Kondo
mesh_terms: D000328:Adult; D000622:Aminolevulinic Acid / Q000652:urine; D002675:Child, Preschool; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D007564:Japan; D008297:Male; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011162:Porphobilinogen / Q000652:urine; D017118:Porphyria, Acute Intermittent / Q000235:genetics* / Q000652:urine; D012326:RNA Splicing
chemical_list: D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase; C048422:endodeoxyribonuclease NlaIII; D015252:Deoxyribonucleases, Type II Site-Specific