Wallace, Daniel Frederick; (1999) The HFE gene in haemochromatosis and liver disease. Masters thesis (M.Sc), UCL (University College London).

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Abstract

Genetic haemochromatosis is an autosomal recessive disorder due to excessive intestinal iron absorption. This leads to accumulation of iron in parenchymal cells and, if untreated, organ damage. The gene (HFE) mutated in the majority of cases was recently identified, allowing non-HFE related haemochromatosis including juvenile haemochromatosis and autosomal dominant haemochromatosis to be recognised. This thesis describes molecular genetic studies in patients with haemochromatosis, a new HFE mutation and an analysis of the contribution of HFE mutations to tissue injury in chronic hepatitis C. Physical mapping of the HFE gene region in genomic DNA was done using pulsed-field gel electrophoresis. HFE mutation analysis was perfomried in the Royal Free Hospital cohort of patients as part of the UK Haemochromatosis Consortium study. The majority were homozygous for the C282Y mutation of HFE. Six Royal Free Hospital patients were not. In these the entire HFE coding region and splice sites were directly sequenced. Five had normal HFE sequence indicating locus heterogeneity of haemochromatosis. The sixth patient, heterozygous for C282Y but with classical haemochromatosis, had a novel splice site mutation (IVS3+1G→T). This mutation is rare. It functionally alters RNA splicing, causing skipping of exon 3 from the mRNA. This predicts loss of the a2 domain from the HFE protein. Finally, the role of HFE mutations and iron in the tissue injury caused by chronic hepatitis C was investigated. Mutations in HFE were not found to predispose to more advanced liver injury. In summary, analysis of the common HFE mutations is important in the diagnosis of haemochromatosis. Other clinically significant mutations rarely occur and may be valuable tools to investigate the biological interactions of the HFE protein. Although HFE mutations theoretically may contribute to hepatic injury from other causes, this has yet to be established.

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