Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria

Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the sp ectrum of sequence variants in the haemochromatosis (HFE) gene, This popula tion screening approach, utilizing a combined heteroduplex and single-stran d conformation polymorphism (HEX-SSCP) method, revealed three previously de scribed and four novel missense mutations. Novel variants V53M and V59M wer e identified in exon 2, Q127H in exon 3 and R330M in exon 5. The exon 5 var iant was identified in one of 13 patients referred for a molecular diagnosi s of hereditary haemochromatosis (HH), who tested negative for the known C2 82Y and H63D mutations. Mutation Q127H was detected in exon 3 of the HFE ge ne together with mutation H63D in an apparently severely affected patient p reviously shown to carry the protoporphyrinogen oxidase (PPOX) gene mutatio n R59W, which accounts for dominantly inherited variegate porphyria (VP) in >80% of affected South Africans. The mutant allele frequency of the C282Y mutation was found to be significantly lower in 73 apparently unrelated VP patients with the R59W mutation than in 102 controls drawn from the same po pulation (P = 0.005). The population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supports prev ious data on the involvement of this gene in the porphyria phenotype,