title: Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice.
abstract: Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaby
authors.forename: Vincent
authors.initials: V
authors.lastname: Oustric
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.forename: Francoise
authors.initials: F
authors.lastname: Muzeau
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Robreau
authors.forename: Philippe
authors.initials: P
authors.lastname: Letteron
authors.forename: Eric
authors.initials: E
authors.lastname: Couchi
authors.forename: Angel
authors.initials: A
authors.lastname: Yu
authors.forename: Saïd
authors.initials: S
authors.lastname: Lyoumi
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Herve
authors.initials: H
authors.lastname: Puy
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Peter
authors.initials: P
authors.lastname: Demant
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002570:Ceruloplasmin / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice / Q000235:genetics* / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci; D012376:Rodent Diseases / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; C522811:Mon1a protein, mouse; D000098742:Ferroportin; D007501:Iron; D002570:Ceruloplasmin