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Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people, or an estimated 600,000 people with HCM in the United States alone. HCM is characterized by left ventricular outflow tract obstruction, diastolic dysfunction, myocardial ischemia and arrhythmias. Strikingly, sudden death among athletes is predominantly associated with HCM. Mutations in sarcomeric genes cause HCM, and mutations in MYBPC3, encoding cardiac myosin binding protein C (cMyBP-C), are responsible for one-third of all HCM cases. However, the pathogenic mechanism of the mutation, whether poison polypeptide or haploinsufficiency, is completely unknown. Recently, studies from the PI’s lab have shown that asymptomatic heterozygous MYBPC3 carriers suffer impairments at the myofilament subset levels and that these impairments may presage the onset of HCM, indicating that haploinsufficiency plays a major role in HCM development, aggressive heart failure, and sudden cardiac death.

The PI and his collaborators previously reported a polymorphic HCM-causing mutation, a 25 base pair (bp) deletion, leading to changes in the C’ region (cMyBP-CC10mut). This specific mutation has been estimated to occur in 55 million people and is associated with the development of HCM and an increased risk of heart failure. Since this mutant gene is present in 4% of South Asian people with a high incidence of heart disease, it may represent a genetic marker providing an early warning for potential heart disease in South Asians. South Asians are individuals who derive their ethnic origins from the Indian Subcontinent, which comprises such countries as India, Pakistan, Bangladesh, Sri Lanka, Nepal and Bhutan, collectively speaking some 150 languages and practicing a variety of spiritual traditions. Often overlooked, South Asians have a high risk of heart attack. This increased risk results from a variety of factors that range from genetics to lifestyle choices. In fact, South Asians have a risk for heart disease 4 times greater than the general population. More specifically, South Asian men and women have a 25- 30% increased risk of heart disease when compared to Caucasians and a 325% increased risk when compared to Chinese. A dominant negative effect of cMyBP-CC10mut on the regulation of contraction is suspected. However, the mechanism by which cMyBP-CC10mut causes cardiomyopathy is unclear. The central hypothesis of this study holds that cMyBP-CC10mut causes contractile dysfunction and leads to the development of HCM.


  • Kuster DW, Govindan S, Springer TI, Martin JL, Finley NL, Sadayappan S. A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction. J Biol Chem. 2015 Jan 12. pii: jbc.M114.607911. [Epub ahead of print]
  • Barefield D, Kumar M, Gorham J, Seidman JG, Seidman CE, de Tombe PP, Sadayappan S. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol. 2015 Feb;79:234-43 (*Accompanied with an editorial article).
  • Barefield D, Kumar M, de Tombe PP, Sadayappan S. Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H807-15.
  • Kuster DW and Sadayappan S. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation. Pflügers Archiv. 2014 466(2):207-13
  • Sequeira V, Wijnker PJ, Nijenkamp LL, Kuster DW, Najafi A, Witjas-Paalberends R, Regan JA, Boontje N, Ten Cate F, Germans T, Carrier L, Sadayappan S,van Slegtenhorst M, Zaremba R, Foster DB, Murphy A, Poggesi C, Dos Remedios CG, Stienen GJ, Ho CY, Michels M, van der Velden J. Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy with Missense Sarcomeric Gene Mutations. Circ Res. 2013;112(11):1491-505
  • Van Dijk SJ, Paalberends ER, Najafi A, Michels M, Sadayappan S, Carrier L, Boontje NM, Kuster D, van Slegtenhorst M., Dooijes D, dos Remedios C, ten Cate FJ, Stienen GJM and van der Velden J. Contractile dysfunction irrespective of the mutant protein in human hypertrophic cardiomyopathy with normal systolic function. Circ Heart Fail. 2012; 5:36-46.
  • Senapathy P, Bhasi A, Mattox J, Dhandapany PS and Sadayappan S. Targeted Genome-Wide Enrichment of Functional Regions. PLoS ONE 2010: 6;5(6):e11138.
  • Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards MB, Price AL, Patterson N, Reich D, Singh L, Tyler-Smith C, Thangaraj K. A common MYBPC3 (cardiac myosin binding protein-C) variant associated with cardiomyopathies in South Asia. Nat Genet. 2009; 41(2):187-191.
  • Dhandapany PS, Sadayappan S, Vanniarajan A, Karthikeyan B, Nagaraj C, Gowrishankar K, Selvam GS, Singh L and Thangaraj K. Novel mitochondrial DNA mutations implicated in Noonan syndrome. Int J Cardiol. 2007; 120(2):284-285.
  • Waldmüller S,* Sakthivel S,* Saadi AV, Selignow C, Rakesh PG, Golubenko M, Joseph PK, Padmakumar R, Richard P, Schwartz K, Tharakan JM, Rajamanickam C and Vosberg HP. Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2003; 35(6):623-636. *Share first authorship equally.
  • Sakthivel S, Vosberg HP and Rajamanickam C. Oligonucleotide ligation assay for rapid and sensitive identification of carriers of a missense mutation in the cardiac β-myosin heavy chain gene causing hypertrophic cardiomyopathy in an Indian family. Current Science. 2001; 80 (12):1588-1592.
  • Chakarova C, Wehnert MS, Uhl K, Sakthivel S, Vosberg HP, Ven PFM and Fürst DO. Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family. Hum Genet. 2000; 107:597-611.
  • Uhl K, Jeschke B, Sakthivel S and Vosberg, H.P. Gamma-filamin gene (FLNC) on chromosome 7, genomic sequence. NCBI DNA databases accession # AF252549.
  • Sakthivel S, Joseph PK, Tharakan JM, Vosberg HP and Rajamanickam C. A novel missense mutation (R712L) adjacent to the "active thiol" region of the cardiac α-myosin heavy chain gene causing hypertrophic cardiomyopathy in an Indian family. Hum Mutat. 1999; 15(3): 298-299.


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