title: Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria.
abstract: Three splicing defects (IVS1+3G-->T, 86A-->T, IVS13-2A-->G), an insertion (416insCA), and two missense mutations (664G-->A and 833T-->G) in the porphobilinogen deaminase (PBGD) gene were identified in six unrelated Finnish patients with acute intermittent porphyria (AIP). The IVS1+3G-->T substitution resulted in activation of a cryptic splice site in intron 1 and retention of a 67-bp fragment in the mutant transcript. The 86A-->T mutation at the end of exon 3 was predicted to cause an amino acid substitution (E29L). However, sequencing of the cDNA sample of the proband revealed exon 3 skipping from the mutant transcript. The IVS13-2A-->G substitution caused retention of intron 13 in the mutant transcript. In exon 8, 416insCA resulted in a frameshift. All three splicing defects and the CA insertion resulted in a truncated protein and thus, probably the loss of PBGD activity. The two novel missense mutations, 664G-->A in exon 12 and 833T-->C in exon 14 caused a single amino acid substitution (V222M and L278P). So far 25 different mutations have been characterized from 37 (93%) of a total of 40 unrelated Finnish AIP families, confirming the genetic heterogeneity of the disease even in a previously isolated area of Finland.
authors.affiliation: Department of Medicine, Helsinki University Central Hospital, Finland. sami.mustajoki@helsinki.fi
authors.forename: S
authors.initials: S
authors.lastname: Mustajoki
authors.forename: H
authors.initials: H
authors.lastname: Pihlaja
authors.forename: H
authors.initials: H
authors.lastname: Ahola
authors.forename: N E
authors.initials: NE
authors.lastname: Petersen
authors.forename: P
authors.initials: P
authors.lastname: Mustajoki
authors.forename: R
authors.initials: R
authors.lastname: Kauppinen
mesh_terms: D004252:DNA Mutational Analysis; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D009154:Mutation; D017118:Porphyria, Acute Intermittent / Q000235:genetics*
chemical_list: D011163:Hydroxymethylbilane Synthase