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Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse ...
BT Ivandic, SE Mastitsky... - Cardiovascular ..., 2012 - 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 ... [HTML]
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 modeling, correlations, gene functional classification, and pathway analysis were conducted using 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 higher than or equal to 0.7) in both males and females.
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Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse ... |
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