Genetic Variation in Titin in Patients with Hypertrophic and Non-Compact Cardiomyopathy

N. N. Chakova; Чакова Н. Н.; R. S. Shulinski; Шулинский Р. С.; S. M. Komissarova; Комиссарова С. М.; T. V. Dolmatovich; Долматович Т. В.; S. S. Niyazova; Ниязова С. С.; O. Ch. Mazur; Мазур О. Ч.; A. S. Ivanova; Иванова А. С.; A. D. Liaudanski; Левданский О. Д.

doi:10.31857/S0016675823070032

Genetic Variation in Titin in Patients with Hypertrophic and Non-Compact Cardiomyopathy

作者: Chakova N.N.¹, Shulinski R.S.¹, Komissarova S.M.², Dolmatovich T.V.¹, Niyazova S.S.¹, Mazur O.C.¹, Ivanova A.S.¹, Liaudanski A.D.¹
隶属关系:
1. Institute of Genetics and Cytology of the National Academy of Sciences of Belarus
2. Republican Scientific and Practical Centre “Cardiology”
期: 卷 59, 编号 7 (2023)
页面: 813-827
栏目: ГЕНЕТИКА ЧЕЛОВЕКА
URL: https://journal-vniispk.ru/0016-6758/article/view/134620
DOI: https://doi.org/10.31857/S0016675823070032
EDN: https://elibrary.ru/QJIMJH
ID: 134620

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详细

Using NGS, the coding sequence of the TTN gene was sequenced in patients with left ventricular non-compaction cardiomyopathy (LVNC, 44 individuals) and hypertrophic cardiomyopathy (HCM, 74 individuals), as well as in the control (194 individuals), and 9 nucleotide variants leading to truncated titin (TTNtv) and 372 missense variants were identified. A comparative analysis of the genetic variability of titin between the groups of patients with LVNC and HCM and the control sample was carried out in terms of the type of mutations and their localization in the exons of genes, as well as in the sarcomeric and functional domains of the protein. The role of TTNtv in the development of LVNC was confirmed, and the significance of additional variants in the same gene or in other genes associated with various cardiomyopathies for the phenotypic implementation of TTNtv was demonstrated. 75% of patients with TTNtv had a dilated LVNC phenotype. Missense substitutions in the TTN gene were found both among the patients with LVNC and HCM, and in people in the control sample, which indirectly confirms that most missense variants in this gene are benign. The paper identifies and lists highly mutable and conserved exons of the TTN gene and also presents a list of missense mutations with possible clinical significance in relation to the structural pathology of the myocardium, including new variants. It was shown that the majority of pathogenic and potentially significant mutations were located in the A-zone of the sarcomere. In all the groups, about 30–50% of new variants were identified. Probably, many of them are neutral and are of exclusively population interest.

关键词

TTN gene, titin-truncating variants (TTNtv), missense-mutations, pathogenic significance of mutations, hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy.

参考

LeWinter M.M., Granzier H.L. Titin is a major human disease gene // Circulation. 2013. V. 127. № 8. P. 938–944. https://doi.org/10.1161/CIRCULATIONAHA.112.139717
Granzier H.L., Irving T.C. Passive tension in cardiac muscle: Contribution of collagen, titin, microtubules, and intermediate filaments // Biophys. J. 1995. V. 68. № 3. P. 1027–1044. https://doi.org/10.1016/S0006-3495(95)80278-X
Bang M.L., Centner T., Fornoff F. et al. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system // Circ Res. 2001. V. 89. № 11. P. 1065–1072. https://doi.org/10.1161/hh2301.100981
Linke W.A. Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction // Cardiovasc. Res. 2008. V. 77. № 4. P. 637–648. https://doi.org/10.1016/j.cardiores.2007.03.029
Musa H., Meek S., Gautel M. et al. Targeted homozygous deletion of M-band titin in cardiomyocytes prevents sarcomere formation // J. Cell Science. 2006. V. 119. № 20. P. 4322–4331. https://doi.org/10.1242/jcs.03198
Lahmers S., Wu Y., Call D.R. et al. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium // Circ. Res. 2004. V. 94. № 4. P. 505–513. https://doi.org/10.1161/01.RES.0000115522.52554.86
Greaser M.L., Krzesinski P.R., Warren C.M. et al. Developmental changes in rat cardiac titin/connectin: Transitions in normal animals and in mutants with a delayed pattern of isoform transition // J. Muscle Res. Cell. Motil. 2005. V. 26. № 6–8. P. 325–332. https://doi.org/10.1007/s10974-005-9039-0
Cazorla O., Freiburg A., Helmes M. et al. Differential expression of cardiac titin isoforms and modulation of cellular stiffness // Circ. Res. 2000. V. 86. № 1. P. 59–67. https://doi.org/10.1161/01.res.86.1.59
Neagoe C., Kulke M., del Monte F. et al. Titin isoform switch in ischemic human heart disease // Circulation. 2002. V. 106. № 11. P. 1333–1341. https://doi.org/10.1161/01.cir.0000029803.93022.93
Nagueh S.F., Shah G., Wu Y. et al. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy // Circulation. 2004. V. 110. № 2. P. 155–162. https://doi.org/10.1161/01.CIR.0000135591.37759.AF
Roberts A.M., Ware J.S., Herman D.S. et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease // Sci. Transl. Med. 2015. V. 7. P. 270–276. https://doi.org/0.1126/scitranslmed.3010134
Herman D.S., Lam L., Taylor M.R. et al. Truncations of titin causing dilated cardiomyopathy // N. Engl. J. Med. 2012. V. 366. № 7. P. 619–628. https://doi.org/10.1056/NEJMoa1110186
Golbus J.R., Puckelwartz M.J., Fahrenbach J.P. et al. Population-based variation in cardiomyopathy genes // Circ. Cardiovasc. Genet. 2012. V. 5. № 4. P. 391–399. https://doi.org/10.1161/CIRCGENETICS.112.962928
Roncarati R., Viviani Anselmi C., Krawitz P. et al. Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy // Eur. J. Hum. Genet. 2013. V. 21. № 10. P. 1105–1111. https://doi.org/10.1038/ejhg.2013.16
Jenni R., Oechslin E., Schneider J. et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: A step towards classification as a distinct cardiomyopathy // Heart (British Cardiac Society). 2001. V. 86. № 6. P. 666–671. https://doi.org/10.1136/heart.86.6.666
Petersen S.E., Selvanayagam J.B., Wiesmann F. et al. // Left ventricular non-compaction: in sights from cardiovascular magnetic resonance imaging // J. Am. College Cardiology. 2005. V. 46. № 1. P. 101–105. https://doi.org/10.1016/j.jacc.2005.03.045
Jacquier A., Thuny F., Jop B. et al. Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular non-compaction // Eur. Heart J. 2010. V. 31. № 9. P. 1098–1104. https://doi.org/10.1093/eurheartj/ehp595
Wang K., Li M., Hakonarson H. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data // Nucl. Acids. Res. 2010. V. 38. № 16. e164. https://doi.org/10.1093/nar/gkq603
Richards S., Aziz N., Bale S. 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. 2015. V. 17. P. 405–424. https://doi.org/10.1038/gim.2015.30
Hazebroek M.R., Krapels I., Verdonschot J. et al. Prevalence of pathogenic gene mutations and prognosis do not differ in isolated left ventricular dysfunction compared with dilated cardiomyopathy // Circ. Heart Fail. 2018. V. 11. № 3. e004682. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004682
Savarese M., Sarparanta J., Vihola A. et al. Increasing role of titin mutations in neuromuscular disorders // J. Neuromuscular Diseases. 2016. V. 3. № 3. P. 293–308. https://doi.org/10.3233/JND-160158
Oates E.C., Jones K.J., Donkervoort S. et al. Congenital titinopathy: Comprehensive characterization and pathogenic insights // Ann. Neurol. 2018. V. 83. № 6. P. 1105–1124. https://doi.org/10.1002/ana.25241
Hinson J.T., Chopra A., Nafissi N. et al. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy // Science. 2015. V. 349. № 6251. P. 982–986. https://doi.org/10.1126/science.aaa5458
Savarese M., Maggi L., Vihola A. Interpreting genetic variants in titin in patients with muscle disorders // JAMA Neurol. 2018. V. 75. № 5. P. 557–565. https://doi.org/10.1001/jamaneurol.2017.4899
Miszalski-Jamka K., Jefferies J.L., Mazur W. et al. Novel genetic triggers and genotype–phenotype correlations in patients with left ventricular noncompaction // Circ. Cardiovasc. Genet. 2017. V. 10. № 4. e001763. https://doi.org/10.1161/CIRCGENETICS.117.001763
Savarese M., Johari M., Johnson K. et al. Improved criteria for the classification of titin variants in inherited skeletal myopathies // J. Neuromuscul. Dis. 2020. V. 7. № 2. P. 153–166. https://doi.org/10.3233/JND-190423
Akinrinade O., Koskenvuo J.W., Alastalo T.P. Prevalence of titin truncating variants in general population // PLoS One. 2015. V. 10. № 12. e0145284. https://doi.org/10.1371/journal.pone.0145284
Begay R.L., Graw S., Sinagra G. et al. Familial cardiomyopathy registry. role of titin missense variants in dilated cardiomyopathy // J. Am. Heart Assoc. 2015. V. 4. № 11. e002645. https://doi.org/10.1161/JAHA.115.002645