Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy
Date of Award
Doctor of Philosophy (PhD)
Heart Failure is one of the leading causes of morbidity and mortality in the human population and represents a common endpoint for several diseases including inherited cardiomyopathies. Hypertrophic Cardiomyopathy (HCM) is characterized by left ventricular wall thickening, diastolic dysfunction, and sarcomere disarray. Mutations in sarcomeric protein encoding genes have been established as causative for HCM.
The gene MYBPC3, encoding cardiac myosin binding protein-C (cMyBP-C), is the second most commonly mutated gene in HCM cases. As a majority of these mutations have been determined to result in a null allele which does not produce any protein, it is thought that haploinsufficiency (i.e. the inability for one allele to express enough protein) causes the development of HCM. In symptomatic heterozygous patients with null MYBPC3 mutations, reduced cMyBP-C levels have been shown. As protein levels in asymptomatic carriers have not been assessed, it is unclear if reduced protein is causative or occurs as a result of the onset of HCM. In this work I tested whether heterozygous (Het) mice expressing a knock-in truncation mutation that expresses normal levels of wild-type (WT) cMyBP-C had altered function, and whether stress-induced hypertrophy resulted in decreased levels of cMyBP-C.
The results of this study show that Het mice have dysfunction under normal conditions and show significantly reduced MYBPC3 expression with preserved cMyBP-C levels. Significant impairments were observed in cardiomyocyte force generation and whole-organ diastolic function in naïve Het mice compared to WT. Following transverse aortic constriction (TAC) pressure-overload cardiac stress, Het mice show significantly greater hypertrophy and reduced cMyBP-C levels compared to WT. Force generation is reduced both in TAC and sham Het cardiomyocytes and significant Ca2+ sensitization is also observed. Finally, deficits in systolic function in vivo are evident in the Het TAC hearts compared to WT TAC.
These findings demonstrate that Het MYBPC3 truncation mutant mice have baseline dysfunction that leads to exacerbated development of hypertrophy and dysfunction following stress. This suggests that human carriers may have functional deficits while appearing asymptomatic, and are predisposed to developing exacerbated hypertrophy with worsened cardiac function.
Barefield, David, "Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy" (2014). Dissertations. 1249.
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Copyright © 2014 David Barefield