DETECTION OF A R173W MUTATION IN THE PORPHOBILINOGEN DEAMINASE GENE IN THE NOVA-SCOTIAN FOREIGN PROTESTANT POPULATION WITH ACUTE INTERMITTENT PORPHYRIA - A FOUNDER EFFECT

Objectives: Acute intermittent porphyria (AIP) is caused by mutations in the porphobilinogen deaminase (PBGD) gene that disrupt the function of the enzyme. Many mutations that lead to decreased PBGD activity ha ve been described. An Arg to Trp substitution at codon 173 (CGG-->TGG in exon 10) and designated R173W, which leads to a GRIM-negative pheno type, has been reported in Swedish, Finnish, Scottish, and South Afric an kindreds, and in a Nova Scotian proband with fatal AIP. In this wor k, we investigated the presence of this mutation in a Nova Scotian pat ient population presenting with AIP. Design and Methods: Single-strand conformation polymorphism analysis and DNA sequencing by TA cloning a nd Sanger's dideoxy chain termination method, were used to confirm the maternal transmission of this mutation to the proband. The mutation a lso eliminates an Ncil (also Mspl) endonuclease restriction site, whic h allows for detection of the mutant allele by polymerase chain reacti on amplification and restriction enzyme digestion. Results: The family of the Nova Scotian proband and four other AIP kindreds showed the pr esence of the same mutation. These five families are descendants of Ge rman, Swiss, and French immigrants historically known as the ''Foreign Protestants,'' who were recruited to Nova Scotia in the 1750s. Conclu sion: In all these families, descent from one couple that settled in N ova Scotia in 1751 has been identified by genealogy research, consiste nt with a founder effect within this population. This is the first ide ntified mutation in PBGD causing AIP that has been linked to a founder effect in descendants of an immigrant population to North America, an d which could be traced to such a distant background, similar to the S outh African variegate porphyria mutation.