Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT？21？mm), a resting left ventricular outflow gradient of 36？mm？Hg, and left atrial dilation (54？mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset. 1. Introduction Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes which encode sarcomeric proteins [1–4]. The most frequently affected genes are MYH7 [5], MYBPC3 [6], and TNNT2 [7], coding for the heavy chain of myosin, the myosin-binding protein-C, and troponin T, respectively. More than 200 mutations have been described in these genes. Furthermore, mutations in a number of other genes, for example, mitochondrial genes [8] have been associated with HCM, albeit at a much lower frequency. Among the rare causes of HCM [9] are mutations in MYL3 which encodes the myosin essential light chain (ELC) of the sarcomere [4, 10–19]. The ELC is located at the lever arm of the myosin head and stabilises this region (Figure 1) through interaction with the IQ1 motif [20, 21] at aminoacid residues 781–810 [22] in beta myosin. The N-terminus of ELC interacts with actin [23]. Although the precise functional role of ELC has not been defined [24], the protein belongs to the EF-hand family of Ca2+-binding proteins [25] and appears to be involved in force development and fine tuning of muscle contraction [26, 27]. The phosphorylation of a C-terminal serine residue has
References
[1]
J. Erdmann, S. Daehmlow, S. Wischke et al., “Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy,” Clinical Genetics, vol. 64, no. 4, pp. 339–349, 2003.
[2]
A. J. Marian, L. Salek, and S. Lutucuta, “Molecular genetics and pathogenesis of hypertrophic cardiomyopathy,” Minerva Medica, vol. 92, no. 6, pp. 435–451, 2001.
[3]
H. Niimura, K. K. Patton, W. J. McKenna et al., “Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly,” Circulation, vol. 105, no. 4, pp. 446–451, 2002.
[4]
P. Richard, P. Charron, L. Carrier et al., “Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy,” Circulation, vol. 107, no. 17, pp. 2227–2232, 2003.
[5]
P. S. Andersen, O. Havndrup, L. Hougs et al., “Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives,” Human Mutation, vol. 30, no. 3, pp. 363–370, 2009.
[6]
P. A. Andersen, O. Havndrup, H. Bundgaard et al., “Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency,” European Journal of Human Genetics, vol. 12, no. 8, pp. 673–677, 2004.
[7]
L. Thierfelder, H. Watkins, C. MacRae et al., “α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere,” Cell, vol. 77, no. 5, pp. 701–712, 1994.
[8]
J. Marín-García, M. J. Goldenthal, and J. J. Filiano, “Cardiomyopathy associated with neurologic disorders and mitochondrial phenotype,” Journal of Child Neurology, vol. 17, no. 10, pp. 759–765, 2002.
[9]
P. S. Andersen, O. Havndrup, H. Bundgaard et al., “Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations,” Journal of Medical Genetics, vol. 38, no. 12, article E43, 2001.
[10]
M. Arad, M. Penas-Lado, L. Monserrat et al., “Gene mutations in apical hypertrophic cardiomyopathy,” Circulation, vol. 112, no. 18, pp. 2805–2811, 2005.
[11]
G. Bonne, L. Carrier, P. Richard, B. Hainque, and K. Schwartz, “Familial hypertrophic cardiomyopathy: from mutations to functional defects,” Circulation Research, vol. 83, no. 6, pp. 580–593, 1998.
[12]
N. D. Epstein, “The molecular biology and pathophysiology of hypertrophic cardiomyopathy due to mutations in the beta myosin heavy chains and the essential and regulatory light chains,” Advances in Experimental Medicine and Biology, vol. 453, pp. 105–115, 1998.
[13]
W. H. Lee, T. H. Hwang, A. Kimura et al., “Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy,” American Heart Journal, vol. 141, no. 2, pp. 184–189, 2001.
[14]
T. M. Olson, M. L. Karst, F. G. Whitby, and D. J. Driscoll, “Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology,” Circulation, vol. 105, no. 20, pp. 2337–2340, 2002.
[15]
K. Poetter, H. Jiang, S. Hassanzadeh et al., “Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle,” Nature Genetics, vol. 13, no. 1, pp. 63–69, 1996.
[16]
J. P. Kaski, P. Syrris, M. T. T. Esteban et al., “Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy,” Circulation, vol. 2, no. 5, pp. 436–441, 2009.
[17]
J. O. Choi, C. W. Yu, J. C. Nah et al., “Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations,” Clinical Cardiology, vol. 33, no. 7, pp. 430–438, 2010.
[18]
S. Fokstuen, A. Munoz, P. Melacini et al., “Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice,” Journal of Medical Genetics, vol. 48, no. 8, pp. 572–576, 2011.
[19]
P. Garcia-Pavia, M. E. Vzquez, J. Segovia et al., “Genetic basis of end-stage hypertrophic cardiomyopathy,” European Journal of Heart Failure, vol. 13, no. 11, pp. 1193–1201, 2011.
[20]
R. Dominguez, Y. Freyzon, K. M. Trybus, and C. Cohen, “Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: visualization of the pre-power stroke state,” Cell, vol. 94, no. 5, pp. 559–571, 1998.
[21]
I. Rayment, W. R. Rypniewski, K. Schmidt-Base et al., “Three-dimensional structure of myosin subfragment-1: a molecular motor,” Science, vol. 261, no. 5117, pp. 50–58, 1993.
[22]
B. Wendel, R. Reinhard, U. Wachtendorf et al., “The human β-myosin heavy chain gene: sequence diversity and functional characteristics of the protein,” Journal of Cellular Biochemistry, vol. 79, no. 4, pp. 566–575, 2000.
[23]
H. R. Trayer and I. P. Trayer, “Differential binding of rabbit fast muscle myosin light chain isoenzymes to regulated actin,” FEBS Letters, vol. 180, no. 2, pp. 170–174, 1985.
[24]
O. M. Hernandez, M. Jones, G. Guzman, and D. Szczesna-Cordary, “Myosin essential light chain in health and disease,” American Journal of Physiology, vol. 292, no. 4, pp. H1643–H1654, 2007.
[25]
Z. Grabarek, “Structural basis for diversity of the EF-hand calcium-binding proteins,” Journal of Molecular Biology, vol. 359, no. 3, pp. 509–525, 2006.
[26]
I. Morano, “Tuning the human heart molecular motors by myosin light chairs,” Journal of Molecular Medicine, vol. 77, no. 7, pp. 544–555, 1999.
[27]
I. Morano, “Tuning smooth muscle contraction by molecular motors,” Journal of Molecular Medicine, vol. 81, no. 8, pp. 481–487, 2003.
[28]
B. Meder, C. Laufer, D. Hassel et al., “A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo,” Circulation Research, vol. 104, no. 5, pp. 650–659, 2009.
[29]
P. Richardson, R. W. McKenna, M. Bristow et al., “Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies,” Circulation, vol. 93, no. 5, pp. 841–842, 1996.
[30]
F. J. Ten Cate, P. G. Hugenholtz, W. G. Van Dorp, and J. Roelandt, “Prevalence of diagnostic abnormalities in patients with genetically transmitted asymmetric septal hypertrophy,” American Journal of Cardiology, vol. 43, no. 4, pp. 731–737, 1979.
[31]
I. A. Adzhubei, S. Schmidt, L. Peshkin et al., “A method and server for predicting damaging missense mutations,” Nature Methods, vol. 7, no. 4, pp. 248–249, 2010.
[32]
A. Houdusse and C. Cohen, “Structure of the regulatory domain of scallop myosin at 2 ？ resolution: implications for regulation,” Structure, vol. 4, no. 1, pp. 21–32, 1996.
[33]
T. A. Hall, “BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT.,” Nucleic Acids Symposium Series, vol. 41, pp. 95–98, 1999.
[34]
M. Terrak, G. Wu, W. F. Stafford, R. C. Lu, and R. Dominguez, “Two distinct myosin light chain structures are induced by specific variations within the bound IQ motifs—functional implications,” The EMBO Journal, vol. 22, no. 3, pp. 362–371, 2003.
[35]
I. Rayment, H. M. Holden, J. R. Sellers, L. Fananapazir, and N. D. Epstein, “Structural interpretation of the mutations in the β-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 9, pp. 3864–3868, 1995.
[36]
E. Moric, U. Mazurek, J. Polońska et al., “Three novel mutations in exon 21 encoding β-cardiac myosin heavy chain,” Journal of Applied Genetics, vol. 44, no. 1, pp. 103–109, 2003.
[37]
J. C. Moolman, P. A. Brink, and V. A. Corfield, “Identification of a novel Ala797Thr mutation in exon 21 of the β-myosin heavy chain gene in hypertrophic cardiomyopathy,” Human Mutation, vol. 6, no. 2, pp. 197–198, 1995.
[38]
M. Enjuto, A. Francino, F. Navarro-López, D. Viles, J. C. Paré, and A. M. Ballesta, “Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in β-myosin heavy chain gene,” Journal of Molecular and Cellular Cardiology, vol. 32, no. 12, pp. 2307–2313, 2000.
[39]
H. Watkins, L. Thierfelder, D. S. Hwang, W. McKenna, J. G. Seidman, and C. E. Seidman, “Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations,” The Journal of Clinical Investigation, vol. 90, no. 5, pp. 1666–1671, 1992.
[40]
C. X. Fang, F. Dong, D. P. Thomas, H. Ma, L. He, and J. Ren, “Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription,” American Journal of Physiology, vol. 295, no. 3, pp. H1206–H1215, 2008.
[41]
A. Moretti, H. J. Weig, T. Ott et al., “Essential myosin light chain as a target for caspase-3 in failing myocardium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11860–11865, 2002.
[42]
V. Rajapurohitam, X. T. Gan, L. A. Kirshenbaum, and M. Karmazyn, “The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes,” Circulation Research, vol. 93, no. 4, pp. 277–279, 2003.
[43]
I. Rayment, H. M. Holden, M. Whittaker et al., “Structure of the actin-myosin complex and its implications for muscle contraction,” Science, vol. 261, no. 5117, pp. 58–65, 1993.
