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The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray

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Abstract

Hypertrophic cardiomyopathy (HCM), a major cause of sudden death in youth, is largely affected by genetic factors. The R58Q mutation in the MYL2 gene was identified in some HCM patients and was considered as a deleterious HCM mutation. However, the passing of R58Q between generations along with HCM symptoms was observed only in small families with only two or three members; thus, whether R58Q is as deleterious as previously claimed remains questionable. Here, we reported a large four-generation Chinese family, and found that R58Q existed in all six members with HCM and two healthy juveniles who had not yet developed HCM yet, and presumably in three deceased members who suffered from sudden death. In addition, we also found that compared with other mutations, R58Q had a more severe effect on the cellular level. Therefore, we confirmed that R58Q could be passed from generation to generation along with HCM symptoms and that it was indeed a deleterious mutation for HCM. However, further study is needed to identify additional factors that may determine the various symptoms shown in different family members within the same family.

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References

  • Ashrafian H, McKenna WJ, Watkins H (2011) Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy. Circ Res 109:86–96

    Article  CAS  Google Scholar 

  • Authors/Task Force m, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H (2014) 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 35:2733–2779

    Article  Google Scholar 

  • Bahcall OG (2015) Genetic testing. ACMG guides on the interpretation of sequence variants. Nat Rev Genet 16:256–257

    Article  CAS  Google Scholar 

  • de la Chapelle A, Tolvanen R, Boysen G, Santavy J, Bleeker-Wagemakers L, Maury CP, Kere J (1992) Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187. Nat Genet 2:157–160

    Article  Google Scholar 

  • Dimitrow PP, Rajtar-Salwa R (2016) Obstructive form of hypertrophic cardiomyopathy-left ventricular outflow tract gradient: novel methods of provocation, monitoring of biomarkers, and recent advances in the treatment. Biomed Res Int 2016:1575130

    Article  Google Scholar 

  • Flavigny J, Richard P, Isnard R, Carrier L, Charron P, Bonne G, Forissier JF, Desnos M, Dubourg O, Komajda M, Schwartz K, Hainque B (1998) Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. J Mol Med (Berl) 76:208–214

    Article  CAS  Google Scholar 

  • Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW, American College of Cardiology Foundation/American Heart Association Task Force on Practice G, American Association for Thoracic S, American Society of E, American Society of Nuclear C, Heart Failure Society of A, Heart Rhythm S, Society for Cardiovascular A, Interventions, Society of Thoracic S (2011) 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 124:2761–2796

    Article  Google Scholar 

  • Ghiso J, Haltia M, Prelli F, Novello J, Frangione B (1990) Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type. Biochem J 272:827–830

    Article  CAS  Google Scholar 

  • Greenberg MJ, Watt JD, Jones M, Kazmierczak K, Szczesna-Cordary D, Moore JR (2009) Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics. J Mol Cell Cardiol 46:108–115

    Article  CAS  Google Scholar 

  • Huang W, Kazmierczak K, Zhou Z, Aguiar-Pulido V, Narasimhan G, Szczesna-Cordary D (2016) Gene expression patterns in transgenic mouse models of hypertrophic cardiomyopathy caused by mutations in myosin regulatory light chain. Arch Biochem Biophys 601:121–132

    Article  CAS  Google Scholar 

  • Kabaeva ZT, Perrot A, Wolter B, Dietz R, Cardim N, Correia JM, Schulte HD, Aldashev AA, Mirrakhimov MM, Osterziel KJ (2002) Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Eur J Hum Genet 10:741–748

    Article  CAS  Google Scholar 

  • Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MG, Bhuiyan Z, Bikker H, Wiesfeld AC, Hauer RN, van Tintelen JP, Jongbloed JD, Calkins H, Judge DP, Wilde AA, Ackerman MJ (2011) Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol 57:2317–2327

    Article  CAS  Google Scholar 

  • Kraft T, Montag J, Radocaj A, Brenner B (2016) Hypertrophic cardiomyopathy: cell-to-cell imbalance in gene expression and contraction force as trigger for disease phenotype development. Circ Res 119:992–995

    Article  CAS  Google Scholar 

  • Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE (1995) Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 92:785–789

    Article  CAS  Google Scholar 

  • Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ (2006) Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation 114:2232–2239

    Article  Google Scholar 

  • Morner S, Richard P, Kazzam E, Hellman U, Hainque B, Schwartz K, Waldenstrom A (2003) Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. J Mol Cell Cardiol 35:841–849

    Article  CAS  Google Scholar 

  • Muthu P, Mettikolla P, Calander N, Luchowski R, Gryczynski I, Gryczynski Z, Szczesna-Cordary D, Borejdo J (2010) Single molecule kinetics in the familial hypertrophic cardiomyopathy D166V mutant mouse heart. J Mol Cell Cardiol 48:989–998

    Article  CAS  Google Scholar 

  • Nunoda S, Genda A, Sekiguchi M, Takeda R (1985) Left ventricular endomyocardial biopsy findings in patients with essential hypertension and hypertrophic cardiomyopathy with special reference to the incidence of bizarre myocardial hypertrophy with disorganization and biopsy score. Heart Vessels 1:170–175

    Article  CAS  Google Scholar 

  • Olivotto I, d’Amati G, Basso C, Van Rossum A, Patten M, Emdin M, Pinto Y, Tomberli B, Camici PG, Michels M (2015) Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations. Cardiovasc Res 105:409–423

    Article  CAS  Google Scholar 

  • Peyrou J, Reant P, Reynaud A, Cornolle C, Dijos M, Rooryck-Thambo C, Landelle M, Montaudon M, Laurent F, Roudaut R, Lafitte S (2016) Morphological and functional abnormalities pattern in hypertrophy-free HCM mutation carriers detected with echocardiography. Int J Cardiovasc Imaging 32:1379–1389

    Article  Google Scholar 

  • Qiu X, Liu W, Hu D, Zhu T, Li C, Li L, Guo C, Liu X, Wang L, Zheng H, Wang C, Diao Q, Shi D, Zhan P, Deng Y, Liu K, Wang Y, Liu B, Liu H, Zhang L (2009) Mutations of plakophilin-2 in Chinese with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Cardiol 103:1439–1444

    Article  CAS  Google Scholar 

  • Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M, Project EHF (2003) Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107:2227–2232

    Article  Google Scholar 

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (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 17:405–424

    Article  Google Scholar 

  • Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O’Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O’Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7:270ra276

    Article  Google Scholar 

  • Semsarian C, Ingles J, Maron MS, Maron BJ (2015) New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 65:1249–1254

    Article  Google Scholar 

  • Sheikh F, Lyon RC, Chen J (2015) Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease. Gene 569:14–20

    Article  CAS  Google Scholar 

  • Tanaka M, Fujiwara H, Onodera T, Wu DJ, Hamashima Y, Kawai C (1986) Quantitative analysis of myocardial fibrosis in normals, hypertensive hearts, and hypertrophic cardiomyopathy. Br Heart J 55:575–581

    Article  CAS  Google Scholar 

  • Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ (2000) Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease. Heart 84:476–482

    Article  CAS  Google Scholar 

  • Wang Y, Xu Y, Kerrick WG, Wang Y, Guzman G, Diaz-Perez Z, Szczesna-Cordary D (2006) Prolonged Ca2+ and force transients in myosin RLC transgenic mouse fibers expressing malignant and benign FHC mutations. J Mol Biol 361:286–299

    Article  CAS  Google Scholar 

  • Wang L, Muthu P, Szczesna-Cordary D, Kawai M (2013) Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q. J Mol Cell Cardiol 62:153–163

    Article  CAS  Google Scholar 

  • Yadav S, Kazmierczak K, Liang J, Sitbon YH, Szczesna-Cordary D (2018) Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain. FEBS J 286:151–168

    Article  Google Scholar 

Download references

Acknowledgements

We sincerely thank Dr. Yuanyuan Fu for the kind proof reading of the manuscript. This work was supported by the Starting Fund for 1000 Youth Talents (no. 2013-RSQ02), the Beijing Science and Technology Program (no. Z161100000516154) and the National Natural Science Foundation of China (no. 81570276).

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Authors and Affiliations

  1. State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Kunlun Yin, Yi Ma, Yang Sun, Bianmei Han, Xuewen Liu, Kun Zhao, Wenke Li, Hongyue Wang & Zhou Zhou

  2. Departments of Cardiovascular Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Hao Cui & Shuiyun Wang

  3. Department of Echocardiography, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Jingjin Wang

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  1. Kunlun Yin
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Correspondence to Shuiyun Wang or Zhou Zhou.

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Conflict of interest

Kunlun Yin declares that he has no conflict of interest. Yi Ma declares that she has no conflict of interest. Hao Cui declares that he has no conflict of interest. Yang Sun declares that she has no conflict of interest. Bianmei Han declares that she has no conflict of interest. Xuewen Liu declares that she has no conflict of interest. Kun Zhao declares that she has no conflict of interest. Wenke Li declares that he has no conflict of interest. Jingjin Wang declares that she has no conflict of interest. Hongyue Wang declares that he has no conflict of interest. Shuiyun Wang declares that he has no conflict of interest. Zhou Zhou declares that he has no competing interests.

Ethical approval

This study was approved by the ethics committee of the institutional review board at Fuwai Hospital. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Communicated by Stefan Hohmann.

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Yin, K., Ma, Y., Cui, H. et al. The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray. Mol Genet Genomics 294, 1241–1249 (2019). https://doi.org/10.1007/s00438-019-01578-4

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