Human Molecular Genetics Advance Access published online on July 15, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg225
© 2003 by Oxford University Press
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1 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Headley Way, Oxford OX3 9DS, UK
* To whom correspondence should be addressed. E-mail: alison{at}hammer.imm.ox.ac.uk.
Haemochromatosis (HH) is a clinically and genetically heterogeneous disease caused by inappropriate iron absorption. Most HH patients are homozygous for the C282Y mutation in the HFE gene. However, penetrance of the C282Y mutation is incomplete, and other genetic factors may well affect the HH phenotype. Ferroportin and TFR2 mutations also cause HH, and a HAMP mutation has recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state. Here, we report evidence for digenic inheritance of HH. We have detected two new HAMP mutations in two different families, in which there is concordance between severity of iron overload and heterozygosity for HAMP mutations when present with the HFE C282Y mutation. In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G). This is a four nucleotide ATGG deletion which causes a frameshift. The proband's unaffected mother is also heterozygous for Met50del IVS2+1(-G), but lacks the C282Y mutation and is heterozygous for the HFE H63D mutation. Met50del IVS2+1(-G) was absent from 642 control chromosomes. In family B, a second novel, less severe HAMP mutation, G71D, was identified. This was detected in the general population at an allele frequency of 0.3%. We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.
Article
Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis
2 Génétique Médicale-CHU, Faculté de Médicine, Université Jules Verne de Picardie, Amiens, France
3 Institute of Liver Studies, Kings College Hospital, London, UK
4 Hépato-gastro-entérologie, Centre Hospitalier Universitaire, Amiens, France
5 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Headley Way, Oxford OX3 9DS, UK; Department of Paediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
6 Department of Pathology, St Peter's Hospital, Chertsey, UK
7 Department of Pathology, Kingston Hospital, Kingston, UK
8 Department of Gastroenterology, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, U.K
9 Department of Paediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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