Hfem1^DBA/2
QTL Variant Detail

Summary

• QTL variant: Hfem1^DBA/2
• Name: Hfe modifier 1; DBA/2
• MGI ID: MGI:3692634
• QTL: Hfem1 Location: unknown Genetic Position: Chr7, cM position of peak correlated region/allele: 17.4 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: DBA/2

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased liver iron content compared to C57BL/6. (J:90494)
• Inheritance: Other (see notes)

Notes

Hfem1 exhibits additive inheritance.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:90494

Linkage analysis was performed on 276 phenotypically extreme Hfe ^tm1Gfn knockout animals from a (C57BL/6-Hfe^tm1Gfn x DBA/2-Hfe ^tm1Gfn)F2 intercross to identify loci associated with susceptibility to iron loading, a subphenotype of hereditary hemochromatosis. Genome scan was performed using 145 microsatellite markers spaced 10 cM - 20 cM apart. Liver iron content was analyzed at 7 weeks of age. Parental strain C57BL/6-Hfe ^tm1Gfn displays significantly higher liver iron content compared to parentalstrain DBA/2-Hfe ^tm1Gfn.

Significant linkage to liver iron content mapped to 16 cM on mouse Chromosome 7 near D7Mit246 (LOD=14.46). This locus explains9.6% of the variance and is named Hfem1 (Hfe modifier 1). DBA/2-derived alleles at Hfem1 confer decreased liver iron with an additive mode of inheritance. Potential candidate genes near this region include Hamp1 (11 cM), Hamp2 (11 cM), and Cebpa (12 cM). Sequence analysis of DBA/2 and C57BL/6 genes revealed 3 amino acid substitutions in Hamp1 and 1 amino acid substitution in Hamp2. Cebpa may influence Hamp1 and Hamp2 expression in response to iron status.

Significant linkage to liver iron content mapped to 49 cM on mouse Chromosome 8 near D8Mit211 (LOD=12.63). This locus explains 8.3% of the variance and is named Hfem2 (Hfe modifier 2). DBA/2-derived alleles at Hfem2 confer increased liver iron content with additive inheritance. Potential candidate genes near Hfem2 include Hmox1 (35 cM), Calr (37 cM), Mt1 (45 cM), Mt2 (45 cM), and Hp (55 cM). A duplication mutation in the Hp gene has known association with iron metabolism in humans.

Hfem3 (Hfe modifier 3) mapped to 29 cM on mouse Chromosome 11 near D11Mit86 (LOD=5.85). This locus explains 5.3% of the variance. DBA/2-derived alleles at Hfem3 confer increased liver iron content with additive or recessive inheritance. Leap2 is a potential candidate gene for Hfem3.

Hfem4 (Hfe modifier 4) mapped to 38 cM on mouse Chromosome 12 near D12Mit158 (LOD=6.32). This locus explains 4.6% of the variance. DBA/2-derived alleles at Hfem4 confer increased liver iron with additive or dominant inheritance.

Suggestive linkage to liver iron content mapped to 12 cM on mouse Chromosome 1 near D1Mit231 (LOD=2.89). DBA/2-derived alleles at D1Mit231 confer decreased liver iron content with recessive inheritance. Authors report Slc39a1 as a candidate gene for the D1Mit231 locus but this gene is located on mouse Chromosome 3 according to mapping data found in the Mouse Genome Database. A second suggestive locus on chromosome 1 was detected at D1Mit206 (LOD=2.48). DBA/2-derived alleles at D1Mit206 confer increased liver iron content with recessive inheritance. Suggestive linkage to liver iron content also mapped to 80.2 cM on mouse Chromosome 3 near D3Mit32 (LOD=2.82). DBA/2-derived alleles at D3Mit32 confer increased liver iron content with additive inheritance.

J:122843

Linkage analysis was performed on 28-29 BXD/Ty (B=C57BL/6J, D=DBA/2J) recombinant inbred (RI) strains to identify genetic loci associated with iron homeostasis. Progenitor strain C57BL/6J displays decreased iron availability, increased iron transport, and increased iron storage values compared to progenitor strain DBA/2J. Animals were sacrificed and phenotyped at 120 days of age.

Proximal mouse Chromosome 5 at 4 Mb displayed linkage to iron availability with a suggestive LOD score of 3.3. The QTL interval spans 5 Mb. Two genes located near this interval are Fzd1 (5 cM) and Pftk1 (0 cM).

Suggestive linkage to iron transport mapped to 146 Mb on mouse Chromosome 1 (LOD=2.2) and 48 Mb on mouse Chromosome 7 (LOD=3.8). The chromosome 1 QTL spans 5 Mb and the chromosome 7 QTL spans 3 Mb. Nearby genes are B830045N13Rik (80 cM, chr1) and Luzp2 (28 cM, chr7), respectively. Hfem1 is a previously identified hemochromatosis modifier QTL located at 30 Mb (16 cM).

Weak linkage to iron storage mapped to 79 Mb on mouse Chromosome 2 with LOD=1.9. This QTL interval spans 3 Mb. Frzb at 49.75 cM is a potential candidate gene for this locus.

References

• Original: J:90494 Bensaid M, et al., Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology. 2004 May;126(5):1400-8
• All: 1 reference(s)