NEW MUTATIONS IN HFE GENE

AFONSO SG, ROSSETTI, MV, BATLLE A, PARERA VE

ST EDMOND HALL, OXFORD, GRAN BRETAÑA

Congreso; TETRAPYRROLE DISCUSSION GROUP; 2006

Hereditary haemochromatosis (HH) is one of the most common inherited metabolic diseases. At present there are 5 types of HH, each linked to a specific gene. HH type I is inherited as an autosomal recessive trait, and the candidate gene (HFE) has been mapped to the short arm of chromosome 6. There are three main muations associated with HH type I: C282Y, H63D and S65C. Iron overload in diffrent organs, mainly in liver, are observed in HH patients, being cirrhosis the most significant manifestation. The disorder is highly prevalent and potentially fatal if untreated when patients carry C282Y mutation in the homozygous form, or both C282Y and H63D mutations  simultaneously in a compound heterozygous form. S65C is responsible for a mild manifestation of HH. Six polymorphisms in exon2 and three in exon 4 have been described. The aim of this work was to anlyze the prevalence of polimorshims in subjects bearing iron metabolism alterations. Amplification and sequencing of exon 2 and 4 of HFE gene were performed in DNA from peripheral blood of 107 individuals (81 males and 26 females), 57% carried mutations in the HFE gen. In exon 4, only E277K polymorphism was present in one individual. In exon 2, two subjects, without mutations in the HFE gene, carried V59M polimorphism. We detected two new mutations/polimorphisms in exon 2: E64Q (190G/C) and R78T (233G/C). The first one was detected in 24 subjects, 5 of them also cariied C282Y mutation (2 in homozygous and 3 in heterozygous form) and 6 of them also carried H63D mutation in heterocigosis. R78T mutation was found in 9 subjects, 2 carried H63D mutation (1 in homozygous and 1 in heterozygous form), 1 carried C282Y mutation in heterozygous and 1 was a compound heterozygous H63D/S65C. Taking into account that only the C282Y mutation in homozygous or heterozygous compound form with H62D are of diagnostic value for HH type I, only in 3 of the 31 individuals analyzed for polymorphism, the molecular study would justify iron metabolism alterations. It is of note that 11 subjects who were heterozygous for any of the reported mutations in the HFE gene, also carried one of these new polymorphisms, which could be reinforcing the effect of only one mutated allele and thus explaining the clinical diagnosis of type I.