title: Multigenic control of hepatic iron loading in a murine model of hemochromatosis.
abstract: OBJECTIVE
  Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading.
  
  
  METHODS
  To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers.
  
  
  RESULTS
  We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism.
  
  
  CONCLUSIONS
  Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.
authors.affiliation: INSERM Unité 563, Centre Hospitalier Universitaire Purpan, F-31059 Toulouse Cedex 3, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Bensaid
authors.forename: Séverine
authors.initials: S
authors.lastname: Fruchon
authors.forename: Christine
authors.initials: C
authors.lastname: Mazères
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
authors.forename: Hélène
authors.initials: H
authors.lastname: Coppin
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008126:Lod Score; D051379:Mice; D018345:Mice, Knockout; D009994:Osmolar Concentration
chemical_list: D007501:Iron