%0 Journal Article %1 Ivandic2012 %A Ivandic, Boris T. %A Mastitsky, Sergey E. %A Schönsiegel, Frank %A Bekeredjian, Raffi %A Eils, Roland %A Frey, Norbert %A Katus, Hugo A. %A Brors, Benedikt %D 2012 %J Cardiovasc Res %K 129 Age Analysis; Animals; Array Association Biology; C3H; C57BL; Cardiomyopathies, Carrier Complex, Computational Congenic; Contraction, Disease; Domain Endopeptidase Expression Factors; Female; Function, Gene Genetic Genome-Wide Inbred Knockout; LIM Left, Male; Mice, Mice; Microfilament Muscle Mutation; Myocardial Nuclear Oligonucleotide Phenotype; Predisposition Profiling, Proteasome Proteins, Proteins; Regulation; Sarcoglycans, Sequence Strain; Study; Transgenic; Ubiquitination; Ubiquitins, Ventricular enzymology/genetics/physiopathology/ultrasonography; genetics genetics/metabolism; genetics; methods; to %N 1 %P 87--95 %R 10.1093/cvr/cvs080 %T Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse strains. %U http://dx.doi.org/10.1093/cvr/cvs080 %V 94 %X 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.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.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.

@article{Ivandic2012, __markedentry = {[bbrors:6]}, abstract = {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.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.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.}, added-at = {2015-04-09T12:36:21.000+0200}, author = {Ivandic, Boris T. and Mastitsky, Sergey E. and Sch{\"{o}}nsiegel, Frank and Bekeredjian, Raffi and Eils, Roland and Frey, Norbert and Katus, Hugo A. and Brors, Benedikt}, biburl = {https://www.bibsonomy.org/bibtex/2f3fbcdd138ba8a850ef3cf6d53ddd2ae/bbrors}, doi = {10.1093/cvr/cvs080}, institution = {Division of Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany. boris.ivandic@synlab.com}, interhash = {334cc0987c97f453e3c2b6c75e6e6885}, intrahash = {f3fbcdd138ba8a850ef3cf6d53ddd2ae}, journal = {Cardiovasc Res}, keywords = {129 Age Analysis; Animals; Array Association Biology; C3H; C57BL; Cardiomyopathies, Carrier Complex, Computational Congenic; Contraction, Disease; Domain Endopeptidase Expression Factors; Female; Function, Gene Genetic Genome-Wide Inbred Knockout; LIM Left, Male; Mice, Mice; Microfilament Muscle Mutation; Myocardial Nuclear Oligonucleotide Phenotype; Predisposition Profiling, Proteasome Proteins, Proteins; Regulation; Sarcoglycans, Sequence Strain; Study; Transgenic; Ubiquitination; Ubiquitins, Ventricular enzymology/genetics/physiopathology/ultrasonography; genetics genetics/metabolism; genetics; methods; to}, language = {eng}, medline-pst = {ppublish}, month = Apr, number = 1, owner = {bbrors}, pages = {87--95}, pii = {cvs080}, pmid = {22308238}, timestamp = {2015-04-09T12:36:21.000+0200}, title = {Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse strains.}, url = {http://dx.doi.org/10.1093/cvr/cvs080}, volume = 94, year = 2012 }