Increased left ventricular mass or hypertrophy (LVH) is an independent risk factor for cardiovascular events. Genetic variation, most commonly in genes encoding the protein constituents of the sarcomere, is an important primary cause of LVH that results in hypertrophic cardiomyopathy (HCM). Genetic studies of HCM patients identify pathogenic mutations in 50-60% of adult-onset familial HCM, ~30% of adult-onset sporadic HCM and ~40% of pediatric-onset HCM. Causes of LVH that clinically presents as HCM in ~50% of adults and children, particularly in those without familial disease, remains unknown. To address this gap in knowledge, we will perform integrated analyses of genomic DNA and cardiac tissue RNA in hypertrophic subjects without a recognized genetic etiology. We will search for undetected germline and somatic variants in the nuclear and mitochondrial genomes through sequenced-based strategies and will consider pathogenic etiologies (Aim 1). To assess the pathogenicity of novel sequence variants and genes we will build upon existing RNAseq datasets to determine if candidate genes participate in hypertrophic signaling pathways and we use high-throughput strategies to modulate candidate gene expression in mice and perform detailed cardiac analyses (Aim 2). Approximately 10% of the general population carries rare non- synonymous variants in sarcomere protein genes without developing overt HCM. To understand discordance in genotype and phenotype, we will map rare non-synonymous, definitive familial HCM mutations and population-identified sarcomere variants on 3-D structures of myofilament proteins, and assess their function in myocytes derived from differentiated isogenic iPS cells (Aim 3). Collectively these studies will expand the repertoire of genetic and acquired causes of HCM and LVH and improve the accurate prediction of phenotypes that arise from rare genetic variation.
Our aims will: 1) Assess genetic variation in cardiac tissue and genomes of patients with LVH using high-throughput DNA sequencing methods. 2) Demonstrate that novel molecules cause or modify LVH in vivo. 3) Define the pathogenicity of rare human sarcomere protein gene variants found in the general population.

Public Health Relevance

Our studies will help understand the causes of inherited and non-inherited heart disease. This understanding should lead to improved diagnostic approaches to left ventricular hypertrophy and will allow patients to benefit from new therapeutic approaches to this condition. Such studies will eventually reduce the medical 'cost'of cardiomyopathy.

National Institute of Health (NIH)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Wang, Lan-Hsiang
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Harvard Medical School
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Ito, Kaoru; Bick, Alexander G; Flannick, Jason et al. (2014) Increased burden of cardiovascular disease in carriers of APOL1 genetic variants. Circ Res 114:845-50
Kurtzwald-Josefson, Efrat; Hochhauser, Edith; Bogachenko, Katia et al. (2014) Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice. Heart Rhythm 11:1471-9
Adalsteinsdottir, Berglind; Teekakirikul, Polakit; Maron, Barry J et al. (2014) Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation. Circulation 130:1158-67
van den Boogaard, Malou; Smemo, Scott; Burnicka-Turek, Ozanna et al. (2014) A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest 124:1844-52
Fatkin, Diane; Seidman, Christine E; Seidman, Jonathan G (2014) Genetics and disease of ventricular muscle. Cold Spring Harb Perspect Med 4:a021063
Dai, Jing; Matsui, Takashi; Abel, E Dale et al. (2014) Deep sequence analysis of gene expression identifies osteopontin as a downstream effector of integrin-linked kinase (ILK) in cardiac-specific ILK knockout mice. Circ Heart Fail 7:184-93
Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian et al. (2014) ?-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res 115:227-37
Jiang, Jianming; Wakimoto, Hiroko; Seidman, J G et al. (2013) Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science 342:111-4
Alcalai, Ronny; Wakimoto, Hiroko; Arad, Michael et al. (2011) Prevention of ventricular arrhythmia and calcium dysregulation in a catecholaminergic polymorphic ventricular tachycardia mouse model carrying calsequestrin-2 mutation. J Cardiovasc Electrophysiol 22:316-24
He, Aibin; Pu, William T (2010) Genome-wide location analysis by pull down of in vivo biotinylated transcription factors. Curr Protoc Mol Biol Chapter 21:Unit 21.20

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