Ancestral founder of mutation W283X in the porphobilinogen deaminase gene among acute intermittent porphyria patients

Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase gene (PBGD). Nearly 60% of all Swiss AIP patients carry a nonsense mutation W283X (G(7916)-->A). In France, the prevalence of W283X is <5%. To determine whether W283X was a founder mutation or originated from multiple de novo events, we studied 25 apparently unrelated W283X families and index patients, 21 of Swiss and 4 of French origins. In the absence of sufficient genealogical data to verify the ancestral background of these W283X families/patients, we identified haplotypes of seven intragenic single nucleotide polymorphisms (SNPs) in the PBGD gene as well as eight microsatellites flanking the PBGD gene covering 9.88 cM in chromosome 11. Molecular cloning and sequencing experiments were required in order to completely resolve the intragenic haplotypes in this study cohort which mainly consisted of single index patients and families with limited members. Thirteen of the 25 W283X families/patients carry a SNP haplotype C-A-A-A-G-C-W283X-G] and 12 (including four French families) carry a T-G-G-G-G-C-W283X-G] haplotype. A less conserved microsatellite haplotype was identified among the 25 W283X alleles which allowed us to estimate the age of the mutation. Since W283X is not explained by a methylcytosine mutation, we favor the hypothesis of a single mutational event which took place on the T-G-G-G-G-C-G] background at approximately 40 generations or 1000 years ago. Around 550 years ago, a recombination event occurred between intron 3 and 10 of the PBGD gene which resulted in the C-A-A-A-G-C-W283X-G] haplotype only found in a restricted region.