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An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1
Author(s) -
Dupradeau FrançoisYves,
Pissard Serge,
Coulhon MariePierre,
Cadet Estelle,
Foulon Karine,
Fourcade Christine,
Goossens Michel,
Case David Andrew,
Rochette Jacques
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9517
Subject(s) - hemochromatosis , hereditary hemochromatosis , biology , compound heterozygosity , mutation , genetics , allele , transferrin , loss of heterozygosity , transferrin receptor , phenotype , gene , receptor , endocrinology
Abstract Most adults affected with HFE hereditary hemochromatosis (HH type 1, MIM♯ 235200) are homozygous for the p.Cys282Tyr mutation in HFE (NC_6.10, region 26195427 to 26205038). The aim of this study was to investigate the molecular basis of iron overload in a patient presenting with severe clinical HH with one c.845G>A (p.Cys282Tyr) allele only. Molecular and pedigree studies demonstrated the presence of the c.845G>A (p.Cys282Tyr) mutation in one allele whereas the other carried the c.187C>G (p.His63Asp) mutation plus a new c.128G>A (p.Gly43Asp) substitution in cis . A molecular modeling study of the p.[Gly43Asp;His63Asp] and p.His63Asp variants versus the wild type was carried out using molecular dynamics (MD) simulation in presence of implicit solvent. We found that the c.187C>G (p.His63Asp) mutation does not introduce any major change in the 1‐ domains of HFE whereas the c.128G>A (p.Gly43Asp) substitution is responsible for a modification of the dynamics and the structure of the Gln40‐Ser45 loop, a critical region for HFE‐TfR1 interaction thus impairing HFE‐TfR1 normal contact. We conclude that the occurrence of complex alleles may be an alternative explanation for the variability of the phenotype in individuals who are compound heterozygous for c.[187C>G]+[845G>A] (p.[His63Asp]+[Cys282Tyr]). © 2007 Wiley‐Liss, Inc.