Mapping Data

Experiment

• Experiment
  TEXT
• Chromosome
  3
• Reference
  J:122133 Gouya L, et al., Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene. Gastroenterology. 2007 Feb;132(2):679-86
• ID
  MGI:3715146

Genes

Gene	Assay Type
Cp	reported elsewhere
D3Mit268	PCR

Notes

• Experiment
  Genetic modifiers of hemochromatosis were mapped using 195 male (C3H/DiSnA x HcB-2/Dem)F2 intercross animals. HcB/-2Dem is a recombinant congenic strain derived from C3H/DiSnA and C57BL/10ScSnA progenitors, and displays lower liver non-heme iron, but similar spleen iron, compared to C3H/DiSnA. Eighteen polymorphic markers were genotyped and strong linkage to liver iron content was detected at 14 cM on mouse Chromosome 3 near D3Mit268 (LOD=48). C3H/DiSnA alleles at this locus confer increased liver iron content.
  
  Cp maps 3 cM distal to D3Mit268 and was investigated as a possible candidate gene. Linkage of Cp to the liver iron phenotype increased the LOD score to 73, and accounted for 85% of the variance. Cp also displays linkage to serum iron (LOD=50) andserum transferritin (LOD=11). The C57BL/10ScSnA-derived allele of Cp appears to be dominant over the C3H/DiSnA-derived allele. Sequence analysis of Cp revealed an exon 7 nonsense mutation (R435X) in C3H/DiSnA resulting in a 10-fold reduction of liver Cp mRNA and the absence of serum ferroxidase activity.
  
  The Hfe^tm1Sly knockout mutation results in elevated liver non-heme iron levels. C3H/DiSnA animals, which are homozygous for the Cp nonsense mutation R435X, display similar liver iron levels as Hfe^tm1Sly knockouts. To investigate the interaction between Cp and Hfe, 195 male (C3H/DiSnA x C3H-Hfe^tm1Sly)F2 animals were analyzed. Homozygous double mutant F2 mice had higher liver iron compared to wild-type or single homozygous mutants, however the effect was not completely additive. Interestingly, animals heterozygous for Cp^R435X and homozygous for Hfe^tm1Sly displayed lower liver iron stores by 30% compared to animals homozygous for only 1 mutation.