Key result
Ubiquitin-proteasome system gene expression strongly correlates with cardiac impairment in mice.
Why the study?
Penetrance and phenotypic expressivity of cardiomyopathies are modulated by modifier genes, but the disease-modifying mechanisms remain to be dissected.
Mouse strain backgrounds modulate cardiomyopathy gene expression; leaves open human modifier variant discovery and risk stratification.
AIMS: Penetrance and phenotypic expressivity of cardiomyopathies are modulated by modifier genes both in model systems and patients. We aimed to dissect the disease-modifying mechanisms by examining genome-wide gene expression in a new set of mouse (Mus musculus) congenic strains. METHODS AND RESULTS: Mutant alleles of the genes calsarcin-1 (Myoz2), sarcoglycan-delta (Sgcd), and muscle LIM protein (Csrp2) were each transferred onto inbred strain backgrounds C57BL/6, C3H/He, 129S1/Sv, and FVB/N, respectively. At 9-10 weeks of age, left ventricular pump function (fractional shortening, FS) was determined by echocardiography in non-sedated congenic animals. Gene expression was then analysed in myocardial tissue using the Affymetrix Mouse 430.2 microarray platform. Variance stabilization, linear mixed-effects modelling, correlations, gene functional classification, and pathway analysis were conducted using the standard software. Strain background FVB/N appeared to protect against the consequences of gene inactivation. Sgcd-deficient congenics showed normal FS, which was consistent with their hypertrophic cardiomyopathy phenotype. Animals with other allele/background combinations developed an impaired ventricular pump function (FS <65%). Gender did not influence FS significantly, yet it determined the sets of genes that were differentially expressed in mice with low FS. In particular, genes encoding the elements of the ubiquitin-proteasome system (UPS) were strongly correlated with the cardiac impairment (absolute Spearman r ≥ 0.7) in both males and females. CONCLUSION: Gene expression profiling in a novel set of congenic strains revealed an association between the UPS and myocardial contractile function, indicating that the UPS may be an important modifier of phenotypic variability in cardiomyopathies.
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Ivandic et al. (2012) studied Cardiomyopathy. Mutant cardiomyopathy alleles on different inbred strain backgrounds was evaluated on Association of gene expression with left ventricular pump function (fractional shortening) (absolute Spearman r ≥ 0.7). Expression of genes encoding elements of the ubiquitin-proteasome system strongly correlated with cardiac impairment (absolute Spearman r ≥ 0.7) in both male and female mice.
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