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MYH7B variants cause hypertrophic cardiomyopathy by activating the CaMK-signaling pathway

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An Erratum to this article was published on 21 October 2021

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Abstract

Hypertrophic cardiomyopathy (HCM) is a common genetic disease, predominantly caused by mutations in cardiac sarcomere genes; however, whether MYH7B causes HCM is not known. In this study, 549 unrelated patients with HCM and 500 healthy-controls were screened using targeted sequencing and whole exome sequencing together. We observed seven variants in MYH7B causing HCM in 8/549 patients, which accounted for 1.46% of HCM cases. Of these seven variants, three likely pathogenic variants in MYH7B co-segregating with 5 HCM patients were identified in three HCM pedigrees without other HCM-associated variants. Myh7b knockout rats were generated and cardiac functions were detected by Millar pressure-volume catheterization and echocardiography. Spontaneous HCM phenotypes, cellular disarray and cardiac fibrosis were observed in both Myh7b+/−/Myh7b−/− rats. Transcriptome sequencing showed that calcium is the key mediator of cardiac hypertrophy in Myh7b knockout. Subsequent analysis confirmed over-activation of CaMK-signaling pathway in cardiomyocytes of Myh7b−/− rats. Furthermore, MYH7B expression in human and rat hearts was identified and microRNA-208a and microRNA-499 levels are unchanged in HCM patients and Myh7b+/−/Myh7b−/− rats. This study is the first to identifyMYH7B variants as cause of HCM, which account for 1.46% of pathogenesisin HCM patients. Activation of CaMK-signaling pathway may be involved in its pathophysiology.

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References

  • Alfares, A.A., Kelly, M.A., McDermott, G., Funke, B.H., Lebo, M.S., Baxter, S.B., Shen, J., McLaughlin, H.M., Clark, E.H., Babb, L.J., et al. (2015). Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med 17, 880–888.

    Article  PubMed  Google Scholar 

  • Black, B.L., and Olson, E.N. (1998). Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 14, 167–196.

    Article  CAS  PubMed  Google Scholar 

  • Braun, A.P., and Schulman, H. (1995). The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol 57, 417–445.

    Article  CAS  PubMed  Google Scholar 

  • Brito, D., Miltenberger-Miltenyi, G., Vale Pereira, S., Silva, D., Diogo, A. N., and Madeira, H. (2012). Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population. Rev Port Cardiol 31, 577–587.

    Article  PubMed  Google Scholar 

  • Cingolani, H.E., and Ennis, I.L. (2007). Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 115, 1090–1100.

    Article  PubMed  Google Scholar 

  • Cingolani, O.H., Yang, X.P., Cavasin, M.A., and Carretero, O.A. (2003). Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats. Hypertension 41, 249–254.

    Article  CAS  PubMed  Google Scholar 

  • Cui, G., Li, Z., Li, R., Huang, J., Wang, H., Zhang, L., Ding, H., and Wang, D.W. (2014). A functional variant in APOA5/A4/C3/A1 gene cluster contributes to elevated triglycerides and severity of CAD by interfering with microRNA 3201 binding efficiency. J Am Coll Cardiol 64, 267–277.

    Article  CAS  PubMed  Google Scholar 

  • Desjardins, C.A., and Naya, F.J. (2016). The function of the MEF2 family of transcription factors in cardiac development, cardiogenomics, and direct reprogramming. J Cardiovasc Dev Dis 3, 26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Desjardins, P.R., Burkman, J.M., Shrager, J.B., Allmond, L.A., and Stedman, H.H. (2002). Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family. Mol Biol Evol 19, 375–393.

    Article  CAS  PubMed  Google Scholar 

  • Elliott, P.M., Anastasakis, A., Borger, M.A., Borggrefe, M., Cecchi, F., Charron, P., Hagege, A.A., Lafont, A., Limongelli, G., Mahrholdt, H., et al. (2014). 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J 35, 2733–2779.

    Article  PubMed  Google Scholar 

  • Esposito, T., Sampaolo, S., Limongelli, G., Varone, A., Formicola, D., Diodato, D., Farina, O., Napolitano, F., Pacileo, G., Gianfrancesco, F., et al. (2013). Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy. Orphanet J Rare Dis 8, 91.

    Article  PubMed  PubMed Central  Google Scholar 

  • Fan, J., Zhang, X., Nie, X., Li, H., Yuan, S., Dai, B., Zhan, J., Wen, Z., Jiang, J., Chen, C., et al. (2019). Nuclear miR-665 aggravates heart failure via suppressing phosphatase and tensin homolog transcription. Sci China Life Sci https://doi.org/10.1007/s11427-018-9515-1.

  • Foster, F.S., Mehi, J., Lukacs, M., Hirson, D., White, C., Chaggares, C., and Needles, A. (2009). A new 15–50 MHz array-based micro-ultrasound scanner for preclinical imaging. Ultrasound Med Biol 35, 1700–1708.

    Article  PubMed  Google Scholar 

  • Frey, N., McKinsey, T.A., and Olson, E.N. (2000). Decoding calcium signals involved in cardiac growth and function. Nat Med 6, 1221–1227.

    Article  CAS  PubMed  Google Scholar 

  • Gersh, B.J., Maron, B.J., Bonow, R.O., Dearani, J.A., Fifer, M.A., Link, M. S., Naidu, S.S., Nishimura, R.A., Ommen, S.R., Rakowski, H., et al. (2011). 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary. J Am Coll Cardiol 58, 2703–2738.

    Article  PubMed  Google Scholar 

  • Gomes, A.V., Potter, J.D., and Szczesna-Cordary, D. (2002). The role of troponins in muscle contraction. IUBMB Life (Int Union Biochem Mol Biol Life) 54, 323–333.

    Article  CAS  Google Scholar 

  • Hook, S.S., and Means, A.R. (2001). Ca2+/CaM-DEPENDENT KINASES: From activation to function. Annu Rev Pharmacol Toxicol 41, 471–505.

    Article  CAS  PubMed  Google Scholar 

  • Kassem, H.S., Azer, R.S., Saber-Ayad, M., Ayad, M.S., Moharem-Elgamal, S., Magdy, G., Elguindy, A., Cecchi, F., Olivotto, I., and Yacoub, M.H. (2013). Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program. J Cardiovasc Trans Res 6, 65–80.

    Article  Google Scholar 

  • Li, B., and Leal, S.M. (2008). Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 83, 311–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, G.R., Lau, C.P., and Shrier, A. (2002). Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol 34, 1185–1194.

    Article  CAS  PubMed  Google Scholar 

  • Li, H., Zhang, X., Wang, F., Zhou, L., Yin, Z., Fan, J., Nie, X., Wang, P., Fu, X.D., Chen, C., et al. (2016). MicroRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation 134, 734–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Z., Huang, J., Zhao, J., Chen, C., Wang, H., Ding, H., Wang, D.W., and Wang, D.W. (2014). Rapid molecular genetic diagnosis of hypertrophic cardiomyopathy by semiconductor sequencing. J Transl Med 12, 173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lopes, L.R., Zekavati, A., Syrris, P., Hubank, M., Giambartolomei, C., Dalageorgou, C., Jenkins, S., McKenna, W., Plagnol, V., and Elliott, P. M. (2013). Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet 50, 228–239.

    Article  CAS  PubMed  Google Scholar 

  • Lu, J., McKinsey, T.A., Nicol, R.L., and Olson, E.N. (2000). Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci USA 97, 4070–4075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahdavi, V., Periasamy, M., and Nadal-Ginard, B. (1982). Molecular characterization of two myosin heavy chain genes expressed in the adult heart. Nature 297, 659–664.

    Article  CAS  PubMed  Google Scholar 

  • Maier, L.S., and Bers, D.M. (2002). Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol 34, 919–939.

    Article  CAS  PubMed  Google Scholar 

  • Maron, B.J., Doerer, J.J., Haas, T.S., Tierney, D.M., and Mueller, F.O. (2009). Sudden deaths in young competitive athletes. Circulation 119, 1085–1092.

    Article  PubMed  Google Scholar 

  • Maron, B.J., Epstein, S.E., and Roberts, W.C. (1986). Causes of sudden death in competitive athletes. J Am Coll Cardiol 7, 204–214.

    Article  CAS  PubMed  Google Scholar 

  • Maron, B.J., McKenna, W.J., Danielson, G.K., Kappenberger, L.J., Kuhn, H.J., Seidman, C.E., Shah, P.M., Spencer Iii, W.H., Spirito, P., Ten Cate, F.J., et al. (2003). American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol 42, 1687–1713.

    Article  PubMed  Google Scholar 

  • Matthijs, G., Souche, E., Alders, M., Corveleyn, A., Eck, S., Feenstra, I., Race, V., Sistermans, E., Sturm, M., Weiss, M., et al. (2016). Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet 24, 2–5.

    Article  CAS  PubMed  Google Scholar 

  • McKinsey, T.A., Zhang, C.L., Lu, J., and Olson, E.N. (2000a). Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKinsey, T.A., Zhang, C.L., and Olson, E.N. (2000b). Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci USA 97, 14400–14405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKinsey, T.A., Zhang, C.L., and Olson, E.N. (2002). MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci 27, 40–47.

    Article  CAS  PubMed  Google Scholar 

  • Mora, R., Merino, J.L., Peinado, R., Olias, F., García-Guereta, L., del Cerro, M.J., Tarín, M.N., and Molano, J. (2006). Hypertrophic cardiomyopathy: infrequent mutation of the cardiac beta-myosin heavy-chain gene (in Spanish). Rev Esp Cardiol 59, 846–849.

    Article  PubMed  Google Scholar 

  • Morita, H., Rehm, H.L., Menesses, A., McDonough, B., Roberts, A.E., Kucherlapati, R., Towbin, J.A., Seidman, J.G., and Seidman, C.E. (2008). Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 358, 1899–1908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morkin, E. (2000). Control of cardiac myosin heavy chain gene expression. Microsc Res Tech 50, 522–531.

    Article  CAS  PubMed  Google Scholar 

  • Peter, A.K., Rossi, A.C., Buvoli, M., Ozeroff, C.D., Crocini, C., Perry, A. R., Buvoli, A.E., Lee, L.A., and Leinwand, L.A. (2019). Expression of normally repressed myosin heavy chain 7b in the mammalian heart induces dilated cardiomyopathy. J Am Heart Assoc 8, e013318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potthoff, M.J., and Olson, E.N. (2007). MEF2: a central regulator of diverse developmental programs. Development 134, 4131–4140.

    Article  CAS  PubMed  Google Scholar 

  • Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–423.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shieh, J.T.C., Huang, Y., Gilmore, J., and Srivastava, D. (2011). Elevated miR-499 levels blunt the cardiac stress response. PLoS ONE 6, e19481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suárez-Pantaleón, C., Huet, A.C., Kavanagh, O., Lei, H., Dervilly-Pinel, G., Le Bizec, B., Situ, C., and Delahaut, P. (2013). Production of polyclonal antibodies directed to recombinant methionyl bovine somatotropin. Anal Chim Acta 761, 186–193.

    Article  PubMed  CAS  Google Scholar 

  • Van Driest, S.L., Ommen, S.R., Tajik, A.J., Gersh, B.J., and Ackerman, M. J. (2005). Yield of genetic testing in hypertrophic cardiomyopathy. Mayo Clinic Proc 80, 739–744.

    Article  Google Scholar 

  • van Rooij, E., Quiat, D., Johnson, B.A., Sutherland, L.B., Qi, X., Richardson, J.A., Kelm Jr., R.J., and Olson, E.N. (2009). A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell 17, 662–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh, R., Buchan, R., Wilk, A., John, S., Felkin, L.E., Thomson, K.L., Chiaw, T.H., Loong, C.C.W., Pua, C.J., Raphael, C., et al. (2017). Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J 38, 3461–3468.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Warkman, A.S., Whitman, S.A., Miller, M.K., Garriock, R.J., Schwach, C. M., Gregorio, C.C., and Krieg, P.A. (2012). Developmental expression and cardiac transcriptional regulation of Myh7b, a third myosin heavy chain in the vertebrate heart. Cytoskeleton 69, 324–335.

    Article  CAS  PubMed  Google Scholar 

  • Watkins, H., Ashrafian, H., and Redwood, C. (2011). Inherited cardiomyopathies. N Engl J Med 364, 1643–1656.

    Article  CAS  PubMed  Google Scholar 

  • Wehbe, N., Nasser, S.A., Pintus, G., Badran, A., Eid, A.H., and Baydoun, E. (2019). MicroRNAs in cardiac hypertrophy. Int J Med Sci 20, 4714.

    CAS  Google Scholar 

  • Zhang, C.L., McKinsey, T.A., and Olson, E.N. (2001). The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci USA 98, 7354–7359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, T., and Brown, J.H. (2004). Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. Cardiovasc Res 63, 476–486.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, J., Yao, H., Li, Z., Wang, L., Liu, G., Wang, D.W., Wang, D.W., and Liang, Z. (2016). A novel nonsense mutation in LMNA gene identified by Exome Sequencing in an atrial fibrillation family. Eur J Med Genet 59, 396–400.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful for all the participants in this study and thank Dr. Chenze Li for statistical analysis. This work was supported by the National Natural Science Foundation of China (81700413, 81630010, 91439203, 91839302), National Key Research and Development Project-Precision Medicine (2017YFC0909401), and Fundamental Research Funds for the Central Universities (No. 2015ZDTD044).

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Authors and Affiliations

  1. Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Peng Chen, Zongzhe Li, Jiali Nie, Hong Wang, Bo Yu, Zheng Wen, Yang Sun, Li Jin & Dao-Wen Wang

  2. Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiological Disorders, Wuhan, 430030, China

    Peng Chen, Zongzhe Li, Jiali Nie, Hong Wang, Bo Yu, Zheng Wen, Yang Sun, Li Jin & Dao-Wen Wang

  3. Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Li Jin & Dao-Wen Wang

  4. Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Xiaolu Shi

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  1. Peng Chen
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Correspondence to Dao-Wen Wang.

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Chen, P., Li, Z., Nie, J. et al. MYH7B variants cause hypertrophic cardiomyopathy by activating the CaMK-signaling pathway. Sci. China Life Sci. 63, 1347–1362 (2020). https://doi.org/10.1007/s11427-019-1627-y

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