Purpose: The purpose of this research is to identify genetic modifiers that interact with the transmembrane protein 135 (Tmem135) gene to cause early sudden death in a transgenic (TG) mouse model overexpressing Tmem135 that exhibits heart abnormalities similar to those in the aged heart. Finding genes that interact with Tmem135 will help elucidate the role of TMEM135 in the early onset and accelerated progression of aging in the heart and death by heart failure.
Introduction: Tmem135 encodes a transmembrane protein that regulates mitochondrial dynamics. Overexpression of Tmem135 causes fragmentation of the mitochondria both in vitro and in vivo in the myocardium. In vivo, Tmem135 overexpression leads to phenotypes in the heart including hypertrophy, collagen accumulation, heart dysfunction, and early adult death, which are similar to abnormalities observed in aged hearts. Furthermore, the gene expression profile of TG hearts is similar to that of the aged mouse hearts. While backcrossing TG mice generated in the FVB background onto the C57BL/6 background, we found that a number of mice die suddenly around postnatal day 21. Increasing the C57BL/6 background increases death in TG mice, suggesting that either the C57BL/6 alleles of the modifiers interact with Tmem135 to cause early sudden death or FVB alleles are protective against sudden death by heart failure.
Methods: To find genetic modifiers contributing to early sudden death, we conducted quantitative trait locus (QTL) analysis in a semi-quantitative fashion using mice generated by the FVB -C57BL/6 intercross and backcross to C57BL/6. A total of 35 mice, 16 of which suffered sudden early death, were genotyped across the genome using 779 markers to differentiate C57BL/6 and FVB alleles. Mice were categorized as either 0, for survival, or 1, for sudden death. Using R/QTL, we conducted a whole-genome scan with 1000 permutations to determine thresholds for selective candidate QTLs.
Results/Conclusion : QTL analysis identified 2 loci on Chromosomes 2 and 17 that affect early sudden death (p =0.014 and p=0.02, respectively). On Chromosome 2, the peak lod score was 4.6 at 51.215 cM. This QTL has a 95% confidence interval between rs4223268 (68.2 cM) and rs1347690 (80.332 cM). On Chromosome 17, the peak lod score was 4.25 at 28.138 cM. This QTL has a 95% confidence interval between rs3696834 (14.38 cM) and rs3657117 (35.6 cM). Based on our results, genes within our identified loci likely interact with Tmem135 to affect sudden death by heart failure in young mice.