Testing modifiers of cardiomyopathy

Project: Research project

Description

Cardiomyopathy carries a significant risk for heart failure, and the two major subtypes are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). HCM and DCM differentially alter cardiac dynamics, with hyperdynamic features as an early presentation in HCM and impaired cardiac function defining DCM. HCM and DCM are strongly influenced by genetics, where the most common form of inheritance is autosomal dominant with variable penetrance and expressivity. Whole genome sequencing from a cohort of HCM and DCM patients identified MTCH2 as a potential modifier gene of cardiomyopathy. The MTCH2 gene encodes a mitochondrial carrier protein, with a known role in repressing oxidative phosphorylation and regulating mitochondrial membrane polarization. In genomewide association studies in humans, MTCH2 single nucleotide polymorphisms have been linked to obesity, indicating a broad effect on metabolism. Deletion of the Mtch2 gene specifically in mouse cardiac and skeletal muscle resulted in increased oxygen consumption and hyperdynamic heart function. We hypothesize that MTCH2 polymorphisms, through loss or reduction in function, increase energy consumption. In the setting of cardiomyopathy this increased energy expenditure is maladaptive. Therefore, the primary goal of this study is to functionally validate the role of MTCH2 dysfunction in cardiomyopathy. To accomplish this, we will develop models of MTCH2 mutations in models of cardiomyopathy. We expect that models with deleted MTCH2 will have increased energy demand. Our long-term goal is to determine the molecular mechanism by which MTCH2 contributes to cardiomyopathy pathogenesis, highlighting a potential mechanism to modulate cardiomyopathy progression.
StatusActive
Effective start/end date1/1/2012/31/21

Funding

  • American Heart Association (20PRE35210837)

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Cardiomyopathies
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Modifier Genes
Penetrance
Mitochondrial Proteins
Oxidative Phosphorylation
Gene Deletion
Mitochondrial Membranes
Oxygen Consumption
Energy Metabolism
Single Nucleotide Polymorphism
Myocardium
Carrier Proteins
Skeletal Muscle
Heart Failure
Obesity
Genome
Mutation
Genes