Abstract 18605: Alterations in Cardiac Transcriptome Induced Dilated Cardiomyopathy and Noncompaction in Mlp-K69R Knock-In Mice

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Abstract

Introduction: The Cysteine and Glycine-Rich Protein 3 (CSRP3) gene encoding muscle LIM protein (MLP) is a master regulator of cardiac muscle myogenesis and mechanosensing. We previously reported that the K69R mutation blocks nuclear import/shuttling of MLP and the entry of myoblasts into myogenesis causing dilated cardiomyopathy (DCM) in homozygous knock-in MlpK69R/K69R mutant mice reminiscent of the human phenotype. Abnormal ventricular wall development in homozygous mutant embryonic hearts at E16.5 indicated noncompaction with DCM.

Hypothesis: Impaired nuclear shuttling of MLP/CSRP3 causes alterations in expression profiles of MLP-binding partner and signaling molecules.

Methods: RNA extracted from 3-month-old male and female heterozygous (MlpWT/K69R), homozygous (MlpK69R/K69R) mutant and WT littermate mouse myocardium was analyzed using Affymetrix Mouse Gene 2.0 ST array. Data were normalized, subjected to systems genetics analysis using GeneNetwork and DAVID bioinformatics resources.

Results: Many sarcomeric genes were significantly overexpressed (P < 0.05) in MlpK69R/K69R mutants compared to WT and MlpWT/K69R littermates. The mutation altered expression of gene networks involved in structural and functional unity of the cytoskeletal sarcomere (Actb, Actc1, Mybpc3, Myl3, Mylk, Tnni, Tnnt, Tnnc1, Actn2), sarcolemma (Dmd, Dag1, Syne1), and desmosomes (Jup). In addition, genes involved in calcium handling (Ryr2, Pln, Cacng1, Cacng6, Atp2a2), LIM-domain and integrin-associated network (Fhl2, Ldb3, Itgb1, Inga1, Ilk) and heart failure (Nppa, Tgfb1) were upregulated in MlpK69R/K69R mutants compared to WT or MlpWT/K69R heterozygote littermates. All of these genes are well known as genes associated with DCM. Interestingly, the Mef2c gene was significantly upregulated in homozygote mutants suggesting a novel candidate gene causing the noncompaction phenotype.

Conclusions: The genes or networks of genes identified have the potential to be used as biomarkers or therapeutic targets for DCM and noncompaction cardiomyopathy. Studies validating and characterizing functional significance of these candidate genes are in a progress.

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