Affiliations: Center for Medical Genetics and Molecular Medicine,
Haukeland University Hospital, N-5021 Bergen, Norway | Norwegian Porphyria Centre, Laboratory of Clinical
Biochemistry, Haukeland University Hospital, N-5021 Bergen, Norway | Porphyria Centre Sweden, CMMS C2-71, Huddinge
University Hospital, SE-141 86 Stockholm, Sweden
Note: [] Corresponding author: Jaran Apold, Center for Medical Genetics
and Molecular Medicine,, University of Bergen, Haukeland University Hospital,
N-5021 Bergen, Norway. Tel.: +47 55 97 54 96; Fax: +47 55 97 54 79; E-mail:
[email protected]
Abstract: Acute intermittent porphyria (AIP), the most common of the acute
porphyrias, is caused by mutations in the gene encoding hydroxymethylbilane
synthase (HMBS) also called porphobilinogen deaminase (PBGD). The mutation
spectrum in the HMBS gene is characterized by a majority of family specific
mutations. Among the exceptions are R116W and W198X, with high prevalence in
both the Dutch and Swedish populations. These two mutations were also detected
in unrelated Norwegian patients. Thus, Norwegian and Swedish patients were
haplotyped using closely linked flanking microsatellites and intragenic single
nucleotide polymorphisms (SNPs) to see if the high frequency of these two
mutations is due to a founder effect. Twelve intragenic SNPs were determined by
a method based on fluorescent restriction enzyme fingerprinting single-strand
conformation polymorphism (F-REF-SSCP). W198X occurred exclusively on one haplotype in both Norwegian and
Swedish patients, showing that it has originated from a common gene source. In
contrast, R116W was found on three different haplotypes in three Norwegian
families, and in five Swedish families on four or five haplotypes. This extreme
haplotype heterogeneity indicates that R116W is a recurrent mutation, maybe
explained by the high mutability of CpG dinucleotides. This can also explain
why it is the only AIP mutation reported to occur in seven different
populations (Norway, Sweden, Finland, Netherlands, France, Spain and South
Africa).
