Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene

Abstract

The sensitivity of single-strand conformation polymorphism (SSCP) analysis for the detection of mutations in the porphobilinogen deaminase (PBGD) gene among Finnish patients with acute intermittent porphyria (AIP) was studied. 13 novel mutations including one de novo event, and six previously characterized mutations were identified among AIP patients. The 19 mutations reported here for 28 families cover 72% of all the AIP families in the Finnish population of five million. When compared to direct sequencing, SSCP-analysis detected 17 (89%) of the 19 mutations when a combination of various electrophoretic conditions were used. The most informative electrophoretic condition was a gel run without glycerol in the coldroom (11/18 mutations). 86% of mutations were identified from amplified fragments greater than 300 bp and detection was dependent on both the amount of glycerol in the gel and the running temperature, but seemed to be independent of the size of the analyzed fragment or the type of mutation. The diagnostic efficiency of biochemical assays versus mutation screening in the PBGD gene was studied in three large AIP families, each representing different CRIM subtypes of AIP. The results demonstrated that using assays of erythrocyte PBGD activity, the majority (82%) of family members (n = 51) were diagnosed correctly. Of a total of 81 family members, 30 of whom had deficiency of PBGD confined to non-erythroid tissues, diagnosis at the asymptomatic stage of disease in 11 individuals (14%) required the application of mutation screening.

HMBS Mutations in Chinese Patients with Acute Intermittent Porphyria

“…Neither clinical symptoms nor the measurement of biochemical parameters are sufficient to confirm disease diagnosis in those individuals experiencing a neurological episode, nor can they be used to identify disease gene carriers (Kauppinen et al, 1995). Molecular genetic approaches therefore offer a better strategy in the diagnosis of this disease in individuals suspected of having an AIP attack.…”

A novel mutation in a family with non-erythroid variant form of acute intermittent porphyria

“…2). These include four point mutations at the exon 1/intron 1 junction of the PBGD gene and one in the initiation of the translation codon of the non-erythroid transcript (Grandchamp et al 1989a,b;Kauppinen et al 1995;Puy et al 1997Puy et al , 1998Chen et al 1994). Three point mutations in the exon 1/intron 1 junction were demonstrated to cause a splicing defect, leading to a 67-bp intronic sequence aberrantly transcribed and a premature stop codon (Puy et al 1998).…”

“…Mutation detection methods used in investigating this variant form of AIP included single-strain conformation polymorphism (SSCP) analysis or denaturing gradient gel electrophoresis (DGGE) followed by DNA sequencing (Chen et al 1994;Kauppinen et al 1995;Puy et al 1997Puy et al , 1998. In view of the fact that all five known mutations causing this variant form of AIP were clustered in a small region of DNA (Fig.…”

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

“…The numbers to the right of the Fig. are sizes in bp. M, DNA size-marker (Kauppinen et al 1995), France (Puy et al 1997), and elsewhere. It is a point mutation modifying codon 173 in exon 10: a C-to-T transition at position 517 led from an arginine to tryptophan substitution (R173W).…”