title: Gene expression patterns in transgenic mouse models of hypertrophic cardiomyopathy caused by mutations in myosin regulatory light chain.
abstract: Using microarray and bioinformatics, we examined the gene expression profiles in transgenic mouse hearts expressing mutations in the myosin regulatory light chain shown to cause hypertrophic cardiomyopathy (HCM). We focused on two malignant RLC-mutations, Arginine 58→Glutamine (R58Q) and Aspartic Acid 166 → Valine (D166V), and one benign, Lysine 104 → Glutamic Acid (K104E)-mutation. Datasets of differentially expressed genes for each of three mutants were compared to those observed in wild-type (WT) hearts. The changes in the mutant vs. WT samples were shown as fold-change (FC), with stringency FC ≥ 2. Based on the gene profiles, we have identified the major signaling pathways that underlie the R58Q-, D166V- and K104E-HCM phenotypes. The correlations between different genotypes were also studied using network-based algorithms. Genes with strong correlations were clustered into one group and the central gene networks were identified for each HCM mutant. The overall gene expression patterns in all mutants were distinct from the WT profiles. Both malignant mutations shared certain classes of genes that were up or downregulated, but most similarities were noted between D166V and K104E mice, with R58Q hearts showing a distinct gene expression pattern. Our data suggest that all three HCM mice lead to cardiomyopathy in a mutation-specific manner and thus develop HCM through diverse mechanisms.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Bioinformatics Research Group (BioRG), School of Computing and Information Sciences, Florida International University, Miami, FL 33199, USA.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kazmierczak
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Bioinformatics Research Group (BioRG), School of Computing and Information Sciences, Florida International University, Miami, FL 33199, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Aguiar-Pulido
authors.affiliation: Bioinformatics Research Group (BioRG), School of Computing and Information Sciences, Florida International University, Miami, FL 33199, USA; Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA.
authors.forename: Giri
authors.initials: G
authors.lastname: Narasimhan
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: dszczesna@med.miami.edu.
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
mesh_terms: D000465:Algorithms; D000818:Animals; D001120:Arginine / Q000737:chemistry; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism*; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D025341:Principal Component Analysis; D014633:Valine / Q000737:chemistry
chemical_list: D018994:Myosin Light Chains; D005973:Glutamine; D018698:Glutamic Acid; D001120:Arginine; D014633:Valine; D008239:Lysine
keywords: Differential gene expression; Microarray; Network/centrality analysis; Pathological hypertrophy; Transgenic mice