Atypical haemochromatosis: phenotypic spectrum and β2-microglobulin candidate gene analysis

β2-microglobulin was investigated in atypical haemochromatosis patients not homozygous for the C282Y mutation of HFE (OMIM *235200), because the HFE protein binds β2-microglobulin, and in mice β2-microglobulin gene knockout causes hepatic iron overload. Six unrelated patients with atypical haemochromatosis were studied. Five patients had normal HFE coding sequence and the sixth was heterozygous for C282Y. We show that the spectrum of atypical haemochromatosis includes two distinct familial forms: juvenile haemochromatosis (OMIM *602390) and a novel form of familial iron overload, with apparently autosomal dominant inheritance, predominant Kupffer cell siderosis, and possible minimal dyserythropoiesis on bone marrow examination. Serial serum β2-microglobulin estimation showed normal levels in all patients. Southern blot analysis showed normal β2-microglobulin gene structure, excluding major gene rearrangement. Several corrections to the published β2-microglobulin sequence were identified, but all six patients had normal β2-microglobulin sequence. Western blot analysis of serum showed β2-microglobulin protein of normal size. In conclusion, we found no evidence to implicate β2-microglobulin mutation in atypical haemochromatosis. Two forms of familial iron overload appear unrelated to either HFE or β2-microglobulin. Linkage studies are required to identify the genes involved, which may encode novel proteins crucial to the regulation of iron metabolism. Identification of these loci will aid the diagnosis, counselling, and treatment of iron overload disorders.

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