title: 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.
abstract: Most adults affected with HFE hereditary hemochromatosis (HH type 1, MIMmusical sharp 235200) are homozygous for the p.Cys282Tyr mutation in HFE (NC_000006.10, 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]).
authors.affiliation: Université de Picardie Jules Verne, UPRES EA 3901 & INSERM E0351, Pôle Santé, Amiens, France.
authors.forename: François-Yves
authors.initials: FY
authors.lastname: Dupradeau
authors.forename: Serge
authors.initials: S
authors.lastname: Pissard
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Coulhon
authors.forename: Estelle
authors.initials: E
authors.lastname: Cadet
authors.forename: Karine
authors.initials: K
authors.lastname: Foulon
authors.forename: Christine
authors.initials: C
authors.lastname: Fourcade
authors.forename: Michel
authors.initials: M
authors.lastname: Goossens
authors.forename: David Andrew
authors.initials: DA
authors.lastname: Case
authors.forename: Jacques
authors.initials: J
authors.lastname: Rochette
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D011990:Receptors, Transferrin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D015703:Antigens, CD; C068126:CD71 antigen; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin