Why the study?
The causal genetic underpinnings of complex congenital heart diseases remain incompletely understood, and genetic causes are sought for patients with HCM who lack mutations in known disease genes.
Does MYOM2 mutation or loss of function cause structural and functional cardiac defects in models of hypertrophic cardiomyopathy and Tetralogy of Fallot?
Does MYOM2 mutation or loss of function cause structural and functional cardiac defects in models of hypertrophic cardiomyopathy and Tetralogy of Fallot?
MYOM2 is identified as a novel candidate gene for hypertrophic cardiomyopathy and Tetralogy of Fallot, playing a critical role in sarcomere integrity and heart development.
MYOM2 mutations may contribute to TOF and HCM; hypothesis-generating and requires functional validation before clinical adoption.
The causal genetic underpinnings of congenital heart diseases, which are often complex and multigenic, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere, and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 [herein referred to as Drosophila myomesin and myosin binding protein (dMnM)] may be an ortholog of MYOM2, as well as other myosin binding proteins. Its partial loss of function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart. This article has an associated First Person interview with Emilie Auxerre-Plantié and Tanja Nielsen, joint first authors of the paper.
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Plantié et al. (2020) studied this question.
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