Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms

Abstract

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS) gene. Although AIP has been identified in all the main ethnic groups, little is known about PBGD gene defects in Africans, Afro-Caribbean and Afro-Americans. We have carried out PBGD gene screening among seven unrelated AIP families and 98 controls belonging to the Afro-Caribbean (French West Indies) and the sub-Saharan African (Morocco, Algeria, Cameroon, Mali, and Burkina Faso) populations. Using denaturing-gradient gel electrophoresis (DGGE) and direct sequencing we characterized six different mutations, including four novel, from the seven AIP families: three splicing defects (IVS 5+2 Ins G; IVS 7+1 G to A in two families; IVS 10-1 G to T); a small deletion (1004 Del G); and two missense mutations (R116 W; A270G). The allele frequencies of the 14 polymorphic sites, previously known in the normal Caucasian population, were similar in Africans and Afro-Caribbean control populations. Interestingly, two common new intragenic polymorphic sites, close to intron/junction boundaries, were identified only in blacks: 1) in intron 2, a single base-pair G deletion at position 3167 (G:0.88; delG:0.12); 2) in intron 10, a A/G dimorphism at position 7052 (A:0.56; G:0.44). These two single nucleotide polymorphisms (SNPs) were never encountered in 750 unrelated Caucasian subjects. The allele frequency distributions of populations within black ethnic groups (Africans and Afro-Caribbean) are similar. This study highlights differences both in PBGD gene mutations causing AIP and in SNPs between white and black peoples; the allele frequencies provided contribute to a better knowledge of the variability of these markers among the major population groups, especially in sub-Saharan West African and Afro-Caribbean populations.

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

“…A study of seven West and North African and Afro-Caribbean patients with AIP characterised six different mutations, four of which were novel 41. In this study, three of the four novel mutations were found in Black or mixed ancestry patients.…”

Mutation hotspots in the human porphobilinogen deaminase gene: Recurrent mutations G111R and R173Q occurring at CpG motifs

“…Single-nucleotide polymorphism (SNP) analysis: Eight SNPs in the PBGD gene, namely 64C/T, 1345A/G, 2479A/G, 3581A/G, 3982C/T, 6479G/T, 7064C/A and 8578G/A, were analysed in all members of the six AIP families (Robreau-Fraolini et al 2000). Except for SNP 3982C/T, methods for determination of the other seven SNPs have been described previously .…”

Ancestral Founder of Mutation W283X in the Porphobilinogen Deaminase Gene among Acute Intermittent Porphyria Patients

“…Of the 14 known SNPs in the PBGD gene, seven were selected for their high heterozygosities (table 2) [13]. Intragenic haplotypes of the seven SNPs cover the PBGD gene of 8.6 kb, starting at position -64 in the promoter region and ending at position 8578 in the 3)-UTR.…”

“…In Great Britain, about 3% of all AIP index cases may have de novo mutations and in France, the rate of de novo mutations was estimated to be 2% [8,12]. In addition to mutations, a total of 16 intragenic single nucleotide polymorphisms (SNPs) have been identified in the PBGD gene, two of which were only observed among the African and AfroCaribbean populations [13].…”