New mutations of the hydroxymethylbilane synthase gene in German patients with acute intermittent porphyria

Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant di sorder caused by decreased activity of hydroxymethylbilane synthase (HMBS; MIM 176 000), the third enzyme in the heme biosynthetic pathway. We report the first molecular analysis of HMBS gene mutations in classical AIP patien ts of German origin. The HMBS gene of 5 German AIP patients was analysed by DGGE-screening and direct sequencing of amplified genomic DNA. Five differ ent mutations including four novel mutations were found. Three of them are single base substitutions that affected exon 3 (R16C), exon 10 (V202L), and intron 13 (T to A, IVS13 +2) The two remaining mutations are frameshifts w hich produce a stop codon (del GA in exon 6 and insA in exon 14). These mut ations are likely to be responsible for the decrease in HMBS activity found in both erythrocytes and non-erythroid cell lines (lymphocytes). Our resul ts demonstrate the allelic heterogeneity of HMBS mutations in AIP patients of German origin. (C) 1999 Academic Press.