Identification of a Founder Mutation in the Protoporphyrinogen Oxidase Gene in Variegate Porphyria Patients from Chile

Abstract

Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disease is usually inherited as an autosomal dominant trait displaying incomplete penetrance. In an effort to characterize the spectrum of molecular defects in VP, we identified 3 distinct mutations in 6 VP families from Chile by PCR, heteroduplex analysis, automated sequencing, restriction enzyme digestion and haplotyping analysis. The mutations consisted of 2 deletions and 1 missense mutation, designated 1239delTACAC, 1330delT and R168H. The occurrence of the missense mutation R168H had been reported previously in American, German and Dutch VP families, suggesting that this may represent a frequent recurrent mutation. Interestingly, the mutation 1239delTACAC was found in patients from 4 unrelated families living in different parts of Chile, suggesting that it might represent a common mutation in Chile. Haplotype analysis using 15 microsatellite markers which closely flank the PPO gene on chromosome 1q22, spanning approximately 21 cM, revealed the presence of R168H on different haplotypes in 6 VP patients from 3 unrelated families. In contrast, we found the occurrence of 1239delTACAC on the same chromosome 1 haplotype in 11 mutation carriers from 4 unrelated families with VP. These findings are consistent with R168H representing a hotspot mutation and 1239delTACAC existing as a founder mutation in the PPO gene. Our data comprise the first genetic studies of the porphyrias in South America and will streamline the elucidation of the genetic defects in VP patients from Chile by allowing an initial screening for the founder mutation 1239delTACAC.

The acute hepatic porphyrias: Current status and future challenges

“…VP (OMIM 176200) is of particular importance in South Africa and Chile where it represents the most frequent type of acute porphyria due to founder effects [9][10][11]14,15]. The incidence of VP in South Africa is the highest in the world, with approximately 1:300 individuals in the white population [9,10].…”

Haplotype Study in Argentinean Variegate Porphyria Patients

“…In effect, an extended haplotype analysis in 3 South African and 3 Dutch families confirmed this hypothesis [8] . Moreover, a common ancestor for a VP mutation based on haplotype analysis has been described for Chilean population [9] .…”

“…These markers were STRs that are flanking the PPOX gene, spanning an interval of 7.1 cM and were selected because they were previously characterized and used in similar studies in other populations [5][6][7][8][9] .…”

“…These markers were selected based on their prior characterization and inclusion in other populations' haplotype VP studies (online suppl. table 2) [5][6][7][8][9] .…”

“…Most of them are private, restrictive to one or a few unrelated VP families. However, there are two prevalent mutations that have been reported in a large number of families in South African and Dutch populations [3][4][5][6][7][8] and a Chilean population [9] , suggesting the existence of a founder effect.…”