transmedТрансляционная медицинаTranslational Medicine2311-44952410-5155Almazov National Medical Research Centre, Saint Petersburg, Russia10.18705/2311-4495-2015-0-2-3-84-89transmed-73Research ArticleЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯEXPERIMENTAL STUDIESРоль мутаций гена notch в развитии пороков сердца и сосудовThe role mutations of notch in cardiac development and congenital heart diseaseТатариноваТатьяна НиколаевнаTatarinovaTatiana N.tatarinova_tn@almazovcentre.ruФрейлихманОльга АлександровнаFreylikhmanO. A.noemail@neicon.ruКостареваАнна АлександровнаKostarevaAnna Aleksandrovnanoemail@neicon.ruИртюгаОльга БорисовнаIrtyugaOlga Borisovnanoemail@neicon.ruМалашичеваАнна БорисовнаMalashichevaAnna Borisovnanoemail@neicon.ruМоисееваОльга МихайловнаMoiseevaOlga Mikhailovnanoemail@neicon.ruФедеральное государственное бюджетное учреждение «Северо-Западный федеральный медицинский исследовательский центр»РоссияNorth-Western Federal Medical Research CenterRussian FederationСеверо-Западный Федеральный Медицинский Исследовательский Центр им. В. А. АлмазоваРоссияNorth-Western Federal Medical Research CenterRussian FederationФедеральное государственное бюджетное учреждение «Северо-Западный федеральный медицинский исследовательский центр»; Санкт-Петербургский государственный университетРоссияNorth-Western Federal Medical Research Center; Saint-Petersburg State UniversityRussian Federation20152312201602-38489Copyright © Татаринова Т.Н., Фрейлихман О.А., Костарева А.А., Иртюга О.Б., Малашичева А.Б., Моисеева О.М., 20162016Татаринова Т.Н., Фрейлихман О.А., Костарева А.А., Иртюга О.Б., Малашичева А.Б., Моисеева О.М.Tatarinova T.N., Freylikhman O.A., Kostareva A.A., Irtyuga O.B., Malashicheva A.B., Moiseeva O.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://transmed.almazovcentre.ru/jour/article/view/73

Высокая частота встречаемости врожденных пороков сердца среди членов одной семьи свидетельствует о существенном вкладе генетического компонента в развитие данной группы заболеваний. В настоящее время доказана роль сигнального пути Notch в кардио- и васкулогенезе, а также выявлена связь мутаций в гене NOTCH1 с формированием врожденных пороков сердца и сосудов. Совершенствование методов пренатальной диагностики, в том числе и путем выявления миссенс-мутаций и редких полиморфных вариантов гена NOTCH1, позволит увеличить вероятность диагностики врожденных пороков сердца у плода, тем самым способствуя своевременному оказанию квалифицированной медицинской помощи и увеличению выживаемости таких пациентов.

The high incidence of congenital heart disease among family members indicates a significant contribution of the genetic component in the development of this group of diseases. An important role of NOTCH1 in cardio-and vasculogenesis as well as a link between mutations in NOTCH1 and congenital heart disease and blood vessels has been suggested recently. It has been proved that Notch signaling plays an important role in the regulation of endothelial-to-mesenchymal transition, which is a critical event in the initial steps forming left ventricle and heart valves. Development of prenatal diagnosis by detecting defects in NOTCH1 gene will increase the probability of fetal congenital heart defects recognition, thereby contributing to the timely provision of skilled care and increasing survival of these patients

NOTCH1эмбриогенезврожденные пороки сердцаNOTCH1embryogenesiscongenital heart diseaseReferencesClementi M, Notari L, Borghi A, et al. Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance. Am J Med Genet. 1996; 62:336-338.Clementi M, Notari L, Borghi A, et al. Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance. Am J Med Genet. 1996; 62:336-338.Huntington KA, Hunter G, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997;30:1809-1812.Huntington KA, Hunter G, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997;30:1809-1812.Pradat P, Francannet C, Harris J, et al. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr Cardiol. 2003;24:195-221.Pradat P, Francannet C, Harris J, et al. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr Cardiol. 2003;24:195-221.Roberts WC. The congenitally bicuspid aortic valve: a study of 85 autopsy cases. Am J Cardiol.1970;26:72-83.Roberts WC. The congenitally bicuspid aortic valve: a study of 85 autopsy cases. Am J Cardiol.1970;26:72-83.Lewin MB, McBride KL, Pignatelli R, et al. Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions. Pediatrics. 2004;114: 691-696.Lewin MB, McBride KL, Pignatelli R, et al. Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions. Pediatrics. 2004;114: 691-696.McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet. 2005; 134A:180-186.McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet. 2005; 134A:180-186.Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270-274.Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270-274.Mohamed SA, Aherrahrou Z, Liptau H, et al. Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun. 2006;345:1460-1465.Mohamed SA, Aherrahrou Z, Liptau H, et al. Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun. 2006;345:1460-1465.McKellar SH, Tester DJ, Yagubyan M, et al. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2007; 134:290-296.McKellar SH, Tester DJ, Yagubyan M, et al. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2007; 134:290-296.McBride K. L., Riley M. F., Zender G.A., et al. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Human Molecular Genetics. 2008;17:(18).McBride K. L., Riley M. F., Zender G.A., et al. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Human Molecular Genetics. 2008;17:(18).Yamamoto S, Schulze KL, Bellen HJ. Introduction to Notch signaling. Methods Mol Biol. 2014;1187:1-14.Yamamoto S, Schulze KL, Bellen HJ. Introduction to Notch signaling. Methods Mol Biol. 2014;1187:1-14.Niessen K., Karsan A. Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol, 2007;293: C1-C11.Niessen K., Karsan A. Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol, 2007;293: C1-C11.Boni A, Urbanek K, Nascimbene A, et al. Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci U S A 2008;105:15529-15534.Boni A, Urbanek K, Nascimbene A, et al. Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci U S A 2008;105:15529-15534.Aanhaanen WT, Moorman AF, Christoffels VM. Origin and development of the atrioventricular myocardial lineage: insight into the development of accessory pathways. Birth Defects Res A Clin Mol Teratol. 2011;91:565-577.Aanhaanen WT, Moorman AF, Christoffels VM. Origin and development of the atrioventricular myocardial lineage: insight into the development of accessory pathways. Birth Defects Res A Clin Mol Teratol. 2011;91:565-577.Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216-233.Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216-233.Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol 2012;23:450-457. doi: 10.1016/j.semcdb. 2012.01.010.Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol 2012;23:450-457. doi: 10.1016/j.semcdb. 2012.01.010.Niessen K., Karsan A. Notch signaling in cardiac development. Circ Res. 2008;102:1169-1181.Niessen K., Karsan A. Notch signaling in cardiac development. Circ Res. 2008;102:1169-1181.High FA, Epstein JA. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet. 2008;9:49-61.High FA, Epstein JA. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet. 2008;9:49-61.Hinton RB, Yutzey KE. Heart valve structure and function in development and disease. Annu Rev Physiol. 2011;73:29-46.Hinton RB, Yutzey KE. Heart valve structure and function in development and disease. Annu Rev Physiol. 2011;73:29-46.Benoit G. Bruneau. The developmental genetics of congenital heart disease. Nature 2008;451(7181):943-948.Benoit G. Bruneau. The developmental genetics of congenital heart disease. Nature 2008;451(7181):943-948.Samanek M., Voriskova M. Infants with critical heart disease in a territory with centralized care. Int. J. Cardiol. 1986;11:63-74.Samanek M., Voriskova M. Infants with critical heart disease in a territory with centralized care. Int. J. Cardiol. 1986;11:63-74.Kelly RG. The second heart field. Curr Top Dev Biol. 2012;100:33-65.Kelly RG. The second heart field. Curr Top Dev Biol. 2012;100:33-65.Neeb Z, Lajiness JD, Bolanis E, Conway SJ. Cardiac outflow tract anomalies.Wiley Interdiscip Rev Dev Biol. 2013 Jul;2 (4):499-530.Neeb Z, Lajiness JD, Bolanis E, Conway SJ. Cardiac outflow tract anomalies.Wiley Interdiscip Rev Dev Biol. 2013 Jul;2 (4):499-530.Schwanbeck R, Martini S, Bernoth K, Just U. The Notch signaling pathway: Molecular basis of cell context dependency. Eur J Cell Biol 2011;90:572-581. doi: 10.1016/j.ejcb.2010.10.004.Schwanbeck R, Martini S, Bernoth K, Just U. The Notch signaling pathway: Molecular basis of cell context dependency. Eur J Cell Biol 2011;90:572-581. doi: 10.1016/j.ejcb.2010.10.004.Timmerman LA, Grego-Bessa J, Raya A, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18:99-115.Timmerman LA, Grego-Bessa J, Raya A, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18:99-115.Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic and functional changes consistent with endothelial-tomesenchymal transformation. Circ Res. 2004;94:910-917.Noseda M, McLean G, Niessen K, et al. Notch activation results in phenotypic and functional changes consistent with endothelial-tomesenchymal transformation. Circ Res. 2004;94:910-917.Riley MF, McBride KL, Cole S. NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT. Biochim Biophys Acta. 2011;1812:121-129.Riley MF, McBride KL, Cole S. NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT. Biochim Biophys Acta. 2011;1812:121-129.Zhou XL and Liu JC. Role of Notch signaling in the mammalian heart. Braz J Med Biol Res 2014; 47(1):1-10.Zhou XL and Liu JC. Role of Notch signaling in the mammalian heart. Braz J Med Biol Res 2014; 47(1):1-10.Epstein JA, de la Pompa JL. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev Cell. 2012;22(2):244-254.Epstein JA, de la Pompa JL. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev Cell. 2012;22(2):244-254.Freylikhman O, Tatarinova T, Smolina N et al. Variants in the NOTCH1 Gene in Patients with Aortic Coarctation. Congenit Heart Dis. 2014 Jan 12. doi: 10.1111/chd.12157.Freylikhman O, Tatarinova T, Smolina N et al. Variants in the NOTCH1 Gene in Patients with Aortic Coarctation. Congenit Heart Dis. 2014 Jan 12. doi: 10.1111/chd.12157.

The authors declare that there are no conflicts of interest present.