Hrtfm4^AKR/J
QTL Variant Detail

Summary

• QTL variant: Hrtfm4^AKR/J
• Name: heart failure modifier 4; AKR/J
• MGI ID: MGI:2686955
• QTL: Hrtfm4 Location: Chr18:60311120-60311343 bp Genetic Position: Chr18, cM position of peak correlated region/allele: 34.36 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: AKR/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased survival and improved fractional shortening compared to DBA/2J. (J:86767)

Notes

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

J:86767

160 microsatellite markers at an average spacing of 15 cM were screened in 100 AKR/J x (AKR/J x DBA/2J-Tg(Myhca-Casq2)1Mord) backcross animals to identify QTLs associated with cardiac function and survival. Parental strain DBA/2J-Tg(Myhca-Casq2)1Mord carries a transgene overexpressing calsequestrin 2 and exhibits dilated cardiomyopathy and premature death. (AKR/J x DBA/2J-Tg(Myhca-Casq2)1Mord)F1 hybrid mice show markedly increased survival and heart function compared to parental DBA/2J-Tg(Myhca-Casq2)1Mord mice, indicating that the AKR/J genetic background provides a protective effect.

Novel QTLs associated with survival mapped to 12 cM on mouse Chromosome 4 (Hrtfm3) and to 35 cM on mouse Chromosome 18 (Hrtfm4). Hrtfm3 spans 8 cM - 18 cM and is centeredat D4Mit236 with LRS=19.9. Hrtfm4 spans 17 cM - 38 cM and is centered at D18Mit28 with LRS=23.6. Hrtfm4 is also linked to fractional shortening (LRS=17.7) and is suggestively linked to left ventricular end diastolic diameter (LRS=9.2). AKR/J-derived alleles confer increased survival at both Hrtfm3 and Hrtfm4. Animals homozygous for AKR/J-derived alleles exhibit greater survival times compared to heterozygotes. In addition, AKR/J-derived alleles confer improved fractional shortening at Hrtfm4. Hrtfm3 explains approximately 10% of the phenotypic variance while Hrtfm4 explains approximately 12% of the phenotypic variance for survival.

Novel QTLs associated with cardiac function mapped to 79 cM on mouse Chromosome 2 (Hrtfm5) and to 59 cM on mouse Chromosome 13 (Hrtfm6). Hrtfm5 spans 67 cM - 98 cM and is centered at D2Mit138 with LRS= 23.5 for left ventricular end diastolic diameter and LRS=22.1 for fractional shortening. Hrtfm6 spans 59 cM - 75 cM and is centered at D13Mit213 with LRS=18.8 for left ventricular end diastolic diameter and LRS=15.2 for fractional shortening. Hrtfm6 is also suggestively linked to survival (LRS=9.5). AKR/J-derived alleles confer improved fractional shortening and left ventricular end diastolic diameter at both Hrtfm5 and Hrtfm6. Hrtfm5 explains approximately 14% of the phenotypic variance for left ventricular end diastolic diameter and approximately 12% of the phenotypic variance for fractional shortening while Hrtfm4 explains approximately 11% of the phenotypic variance for leftventricular end diastolic diameter and approximately 8% of the phenotypic variance for fractional shortening.

Interaction was observed between Hrtfm4 and Hrtfm6 affecting fractional shortening (LRS=34.6). Animals homozygous for AKR/J-derived alleles at both Hrtfm4 and Hrtfm6 exhibit improved fractional shortening.

Interaction between Hrtfm4 and a locus at D19Mit88 (34 cM) was detected (LRS=26.5). The D19Mit88 locus has no effect by itself but rather enhances the effect of Hrtfm4 on fractional shortening. Animals homozygous for AKR/J-derived alleles at both Hrtfm4 and D19Mit88 exhibit improved fractional shortening.

References

• Original: J:86767 Le Corvoisier P, et al., Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy. Hum Mol Genet. 2003 Dec 1;12(23):3097-107
• All: 1 reference(s)