MUTATIONS AND RARE VARIANTS OF DESMIN GENE AS THE CAUSE OF DIFFERENT CARDIOMYOPATHIES

Objective. Several desmin mutations have been described over the past years in patients with dilated and restrictive cardiomyopathy, often in association with distal myopathy. However, the role of desmin mutations as a cause of various types of cardiomyopathy is still undetermined. The aim of this study was to analyse the frequency of desmin mutations in patients with dilated, hypertrophic and restrictive cardiomyopathy identified and diagnosed in the St. Petersburg area of Russia. Material, methods and results. We screened 98 patients with dilated, 40 with hypertrophic and 20 with restrictive cardiomyopathy. All exons of the desmin gene were amplified by PCR and studied by sequencing. Two of 98 patients with dilated cardiomyopathy and 1 patient with restrictive cardiomyopathy showed the presence of desmin gene mutations, not previously described. An A213V shift, suspected to represent a conditional mutation, was associated with a case of late-onset dilated cardiomyopathy. Functional studies confirmed mild structural defect caused by A213V variant and revealed by desmin and vimentin staining. No desmin mutations were found in patients with hypertrophic cardiomyopathy. We conclude that desmin mutations should be considered a relatively rare cause of dilated and restrictive cardiomyopathy. Rare desmin variant A213V causes mild structural defect on intracellular intermediate filament network.

кардиомиопатия, мутация, десмин, трансфекция, промежуточные филаменты, cardiomyopathy, desmin, mutation, transfection, intermediate filaments

1. Towbin J.A., Hejtmancik J.F., Brink P et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus // Circulation. - 1993. - Vol. 87, № 6. - P. 1854-1865.

2. Li D., Tapscoft T., Gonzalez O. et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy // Circulation. - 1999. - Vol. 100, № 5. - P. 461-464.

3. 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. - Vol. 21, № 3. - P. 285-288.

4. Sanna T., Dello Russo A., Toniolo D. et al. Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations // Eur. Heart J. - 2003. - Vol. 24, № 24. - P. 2227-2236.

5. Mogensen J., Kubo T., Duque M. et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations // J. Clin. Invest. - 2003. - Vol. 111, № 2. - P. 209-216.

6. Goldfarb L.G., Vicart P., Goebel H.H., Dalakas M.C. Desmin myopathy // Brain. - 2004. - Vol. 127, Pt. 4. - P. 723-734.

7. Tesson F., Sylvius N., Pilotto A. et al. Epidemiology of desmin and cardiac actin gene mutations in a european population of dilated cardiomyopathy // Eur. Heart J. - 2000. - Vol. 21, № 22. - P. 1872-1876.

8. Miyamoto Y., Akita H., Shiga N. et al. Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population // Eur. Heart J. - 2001. - Vol. 22, № 24. - P. 2284-2289.

9. Vicart P., Dupret J.M., Hazan J. et al. Human desmin gene: cDNA sequence, regional localization and exclusion of the locus in a familial desmin-related myopathy // Hum. Genet. - 1996. - Vol. 98, № 4. - P. 422-429.

10. Goldfarb L.G., Park K.Y., Cervenakova L. et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy // Nat. Genet. - 1998. - Vol. 19, № 4. - P. 402-403.

11. Ющенко M.B., Новик Г.А., Костарева А.А., Гудкова А.Я. Особенности течения кардиомиопатий, обусловленных мутациями гена тропонина I // Артериальная гипертензия. - 2009. - Т. 15, № 5. - С. 648-651.

12. Richard P., Charron P., Carrier L. et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy // Circulation. - 2003. - Vol. 107, № 17. - P. 2227-2232.

13. Muntoni F., Catani G., Mateddu A. et al. Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments // Neuromuscul. Disord. - 1994. - Vol. 4, № 3. - P. 233-241.

14. Porcu M., Muntoni F., Catani G., Mereu D. Familial cardiac and skeletal myopathy associated with desmin accumulation // Clin. Cardiol. - 1994. - Vol. 17, № 5. - P. 277-279.

15. Olive M., Goldfarb L., Moreno D. et al. Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies // J. Neurol. Sci. - 2004. - Vol. 219, № 1-2. - P. 125-137.

16. Osterziel K.J., Perrot A. Dilated cardiomyopathy: more genes means more phenotypes // Eur. Heart J. - 2005. - Vol. 26, № 8. - P. 751-754.

17. Thornell L.E., Eriksson A. Filament systems in the Purkinje fibers of the heart // Am. J. Physiol. - 1981. - Vol. 241, № 3. - P. H291-305.

18. Park K.Y., Dalakas M.C., Goebel H.H. et al. Desmin splice variants causing cardiac and skeletal myopathy // J. Med. Genet. - 2000. - Vol. 37, № 11. - P. 851-857.

19. Munoz-Marmol A.M., Strasser G., Isamat M. et al. A dysfunctional desmin mutation in a patient with severe generalized myopathy // Proc. Natl. Acad. Sci. USA. - 1998.- Vol. 95, № 19. - P. 11312-11317.

20. Bowles N.J.S., Vatta M., Chrisco M. et al. Familial restrictive cardiomyopathy caused by missense mutation in the desmin gene. // Pediatric Research. - 2002. - Vol. 51, Suppl. 2.

21. Schroder R., Goudeau B., Simon M.C. et al. On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria // Hum. Mol. Genet. - 2003. - Vol. 12, № 6. - P. 657-669.

22. Park K.Y., Dalakas M.C., Semino-Mora C. et al. Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation // Clin. Genet. - 2000. - Vol. 57, № 6. - P. 423-429.

23. Sjoberg G., Saavedra-Matiz C.A., Rosen D.R. et al. A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation // Hum. Mol. Genet. - 1999. - Vol. 8, № 12. - P. 2191-2198.

24. Kaminska A., Strelkov S.V., Goudeau B. et al. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy // Hum. Genet. - 2004. - Vol. 114, № 3. - P. 306-313.

25. Dalakas M.C., Park K.Y., Semino-Mora C. et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene // N. Engl. J. Med. - 2000. - Vol. 342, № 11. - P. 770-780.

26. Sugawara M., Kato K., Komatsu M. et al. A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates // Neurology. - 2000. - Vol. 55, № 7. - P. 986-990.

27. Kostareva A., Sjoberg G., Gudkova A. et al. Desmin A213V substitution represents a rare polymorphism but not a mutation and is more prevalent in patients with heart dilation of various origins // Acta Myol. - 2011. - Vol. 30, № 1. - P. 42-45.

28. Смолина Н.А., Щукина И.А., Карпушев А.В. и др. Сравнительная оценка методов получения функционально активных дифференцированных мышечных клеток // Цитология. - 2014. - Т. 56, № 4. - С. 291-299.