МУТАЦИИ ГЕНА ЛАМИНА A/C (LMNA) У ПАЦЕНТОВ С ДИЛАТАЦИОННОЙ КАРДИОМИОПАТИЕЙ И ИХ ФЕНОТИПИЧЕСКИЕ ПРОЯВЛЕНИЯ

В статье приведены современные представления о структуре и функциях ядерных белков ламинов, патологические механизмы генных ламиновых мутаций и лечебно-диагностические проблемы ламин-ассоциированных форм дила-тационной кардиомиопатии (ДКМП). ДКМП, обусловленная мутациями ядерного гена ламина (LMNA), часто связана с нарушениями сердечного ритма, проводимости и различными скелетно-мышечными расстройствами. Это заболевание отличается неблагоприятным прогнозом, обусловленным высоким риском внезапной сердечной смерти из-за нарушений проводимости (жизнеугрожающие блокады) или желудочковой тахиаритмии (фатальные желудочковые тахикардии/ фибрилляции). В статье представлены 2 клинических случая ламиновых фенотипов ДКМП, ассоциированных с мутациями гена LMNA. В обучающем аспекте для практических врачей изложены дифференциальные клинические признаки потенциальных носителей LMNA мутаций, так как генетическая диагностика ламиновых ДКМП позволяет своевременно определить оптимальную тактику лечения и необходимость профилактической имплантации кардиовертера-дефибрил-лятора.

1. Burke B, Stewart CL. Life at the edge: the nuclear envelope and human disease. Nat Rev Mol Cell Biol 2002; 3:575-585

2. Cohen M, Lee KK, Wilson KL, Gruenbaum Y. Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina. Trends Biochem Sci 2001; 26:41-47

3. Lammerding J, Schulze PC, Takahashi T et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 2004;113(3): 370-8

4. Hutchison CJ. Lamins: building blocks or regulators of gene expression? Nat Rev Mol Cell Biol 2002; 3(11): 848-58

5. Lin F, Worman HJ. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem 1993; 268:16321-16326

6. Dechat T. Nuclear lamins: Major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 2008; 22: 832-853.

7. Mattout A, Dechat T, Adam S A, Goldman and Gruenbaum Y. Nuclear lamins, diseases and aging//Current Opinion in Cell Biology 2006,18:335-341

8. Meshorer E, Gruenbaum Y. Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging. J Cell Biol 2008; 181(1): 9-13

9. Moir R., Yoon M., Khuon S., Goldman R. Nuclear lamins A and B1: Different pathways of assembly during nuclear envelope formation in living cells. J Cell Biol 2000;151:1155-1168

10. Shimi T, Pfleghaar K, Kojima S, et al. The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription //Genes Dev 2008; 22(24): 3409-3421

11. Guelen, L., Pagie, L., Brasset, E., et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 2008; 453:948-951

12. Rajendran V., Purohit R., Sethumadhavan R. In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein. Amino Acids 2012; 43 (2): 603-615

13. Bonne G., Di Barletta M.R., Varnous S. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999; 21:285-288

14. Fatkin D., MacRae C., Sasaki T. et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715-1724

15. Worman H., Ostlund C., Wang Y. Diseases of the nuclear envelope. Cold Spring Harb Perspect. Biol 2010; 2:760-776

16. Houben F. De Vos W. H. Krapels I. P. et al. Cytoplasmic localization of PML particles in laminopathies. Histochem Cell Biol 2013; 139:119-134

17. Hutchison CJ, Alvarez-Reyes M, Vaughan OA. Lamins in disease: why do ubiquitously expressed nuclear envelope proteins give rise to tissue-specific disease phenotypes? J Cell Sci 2001; 114(1): 9-19

18. Wilson KL, Zastrow MS, Lee KK. Lamins and disease: insights into nuclear infrastructure. Cell 2001; 104(5): 647-650

19. Schirmer EC, Foisner R. Proteins that associate with lamins: many faces, many functions. Exp Cell Res 2007; 313(10): 2167-2179

20. De Vos WH, Houben F, Kamps MV et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet 2011; 20:4175-4186

21. Dhe-Paganon S1, Werner ED, Chi YI, Shoelson SE. J Structure of the globular tail of nuclear lamin. Biol Chem 2002; 277(20): 17381-17384.

22. Verdaguer N, Corbalan-Garcia S, Ochoa WF Fita et al. Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine. J EMBO 1999; 18(22): 6329-6338

23. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals. Genet Med 2010; 12:655-667

24. Van Tintelen J. Peter , Petronella G. Pieper, Karin Y. Van Spaendonck-Zwarts et al. Pregnancy, cardiomyopathies, and genetics. Cardiovascular Research 2014; 101:571-578

25. Jacoby D, McKenna WJ. Genetics of inherited cardiomyopathy. Eur Heart J 2012; 33:296-304

26. Fatkin D, Otway R, Richmond Z. Genetics of dilated cardiomyopathy. Heart Fail Clin 2010; 6:129-140

27. R.Weichenhan, T.M.Strom, A.Pfeufer et al. Cardiomyopathies. Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomiopathies. J Circ Cardiovasc Genet 2011; 4:110-122

28. Van Berlo JH, Meune C, Anselme F et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations port end a high risk of sudden death? J Mol Med 2005; 83:79-83

29. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250-1260

30. Ph.Charron, E. Arbustini, G. Bonne. What Should the Cardiologist know about Lamin Disease? Arrhythmia & Electrophysiology 2012; 1:22-28

31. Parks SB, Kushner JD, Nauman D et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. A. Heart J 2008; 56:161169

32. Meune C, Van Berlo JH, Anselme F et al. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006; 354:209-210

33. Fernandez X, Dumont CA, Monserrat L et al. Sudden death in a patient with lamin A/C gene mutation and near normal left ventricular systolic function. Int J Cardiol 2008; 126: 136137

34. Ehlermann P, Lehrke S, Papavassiliu T, et al. Sudden cardiac death in a patient with lamin A/C mutation in the absence of dilated cardiomyopathy or conduction disease. Clin Res Cardiol 2011; 100:547-551

35. Van Rijsingen IA, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin A/C mutation carriers a European cohort study. J Am Coll Cardiol 2012; 59: 493-500

36. Charron P, Arad M, Arbustini E, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2010; 1:2715-2726

37. Frey N, Katus HA. Dilated cardiomyopathy as a genetic disease: molecular and clinical aspects. Internist 2008: 49: 43-50

38. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals. Genet. Med 2010; 12:655-667

39. Jacoby D, McKenna WJ. Genetics of inherited cardiomyopathy. Eur. Heart J 2012; 33:296-304

40. Fatkin D, Otway R, Richmond Z. Genetics of dilated cardiomyopathy. Heart Fail. Clin 2010; 6:129-140

41. Hugh Watkins, Houman Ashrafian, D.Phil., Charles Fedwood. Inherited Cardiomyopathies. New Engl. J Medicine 2011; 364(17): 1643-1656

42. Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am. Coll. Cardiol 2011; 57:1641-1649

43. Вайханская Т.Г., Сивицкая Л.Н, Даниленко Н.Г. и соавт. Что должен знать сегодня кардиолог о дилатационной кардиомиопатии, связанной с мутацией гена ламина (LMNA)? Кардиология в Беларуси 2013; 4 (29): 64-81.