The causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, 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 may be an ortholog of MYOM2, as well as other myosin binding proteins (henceforth named as Drosophila Myomesin and Myosin Binding protein (dMnM)). 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.

中文翻译：

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MYOM2作为肥厚型心肌病和法洛四联症候选基因的鉴定及其在果蝇心脏中的功能评估。

先天性心脏病的因果遗传基础通常很复杂且具有多基因背景，但仍远未了解。此外，还存在主要是单基因心脏缺陷，例如心肌病，大多数病例具有已知的疾病基因。在这项研究中，我们在法洛四联症 (TOF)（最常见的紫绀型心脏畸形）患者以及肥厚型心肌病 (HCM) 患者中发现了肌球蛋白 2 (MYOM2) 突变，这些患者的肌球蛋白 2 (MYOM2) 未表现出任何突变。已知的疾病基因。MYOM2 是肌节肌原纤维 M 带的主要组成部分，也是肌节基因相互作用中的枢纽基因。我们发现，患者来源的心肌细胞表现出肌原纤维紊乱，并且随着肌节长度的增加，被动力降低。此外，我们对果蝇动物模型的全面功能分析表明，迄今为止尚未表征的果蝇基因CG14964可能是MYOM2以及其他肌球蛋白结合蛋白（以下称为果蝇M yomesin 和d Myosin结合蛋白（dMnM ) ) 。其部分功能丧失或中度心脏抑制会导致心脏扩张，而更严重的功能下降会导致表型收缩和肌节肌球蛋白增加。此外， CG14964和肌节基因Mhc（MYH6/7 ）的复合杂合组合表现出协同遗传相互作用。总之，我们的结果表明，MYOM2不仅在维持强健的心脏功能中发挥着关键作用，而且还可能是HCM和TOF等心脏病的候选基因，因为它明显参与了心脏的发育。