Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse strains.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Division of Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany. boris.ivandic@synlab.com
Boris T
BT
Ivandic
Sergey E
SE
Mastitsky
Frank
F
Schönsiegel
Raffi
R
Bekeredjian
Roland
R
Eils
Norbert
N
Frey
Hugo A
HA
Katus
Benedikt
B
Brors
D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000235:genetics*
D002352:Carrier Proteins; C484376:Csrp2 protein, mouse; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C523646:Myoz2 protein, mouse; D009687:Nuclear Proteins; D049031:Sarcoglycans; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex