Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2000 Nov;37(11):851–857. doi: 10.1136/jmg.37.11.851

Desmin splice variants causing cardiac and skeletal myopathy

K Park 1, M Dalakas 1, H Goebel 1, V Ferrans 1, C Semino-Mora 1, S Litvak 1, K Takeda 1, L Goldfarb 1
PMCID: PMC1734475  PMID: 11073539

Abstract

Desmin myopathy is a hereditary or sporadic cardiac and skeletal myopathy characterised by intracytoplasmic accumulation of desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene desmin resulting in deletion of the entire exon 3 during the pre-mRNA splicing. Sequencing of cDNA and genomic DNA identified a heterozygous de novo A to G change at the +3 position of the splice donor site of intron 3 (IVS3+3A→G) in a patient with sporadic skeletal and cardiac myopathy. A G to A transition at the highly conserved -1 nucleotide position of intron 2 affecting the splice acceptor site (IVS2-1G→A) was found in an unrelated patient with a similar phenotype. Expression of genomic DNA fragments carrying the IVS3+3A→G and IVS2-1G→A mutations confirmed that these mutations cause exon 3 deletion. Aberrant splicing leads to an in frame deletion of 32 complete codons and is predicted to result in mutant desmin lacking 32 amino acids from the 1B segment of the alpha helical rod. Functional analysis of the mutant desmin in SW13 (vim-) cells showed aggregation of abnormal coarse clumps of desmin positive material dispersed throughout the cytoplasm. This is the first report on the pathogenic potentials of splice site mutations in the desmin gene.


Keywords: cardiac and skeletal myopathy; desmin splice site mutations; expression study; genotype-phenotype correlation

Full Text

The Full Text of this article is available as a PDF (193.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Capetanaki Y., Milner D. J., Weitzer G. Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct Funct. 1997 Feb;22(1):103–116. doi: 10.1247/csf.22.103. [DOI] [PubMed] [Google Scholar]
  2. De Bleecker J. L., Engel A. G., Ertl B. B. Myofibrillar myopathy with abnormal foci of desmin positivity. II. Immunocytochemical analysis reveals accumulation of multiple other proteins. J Neuropathol Exp Neurol. 1996 May;55(5):563–577. doi: 10.1097/00005072-199605000-00009. [DOI] [PubMed] [Google Scholar]
  3. Fuchs E., Weber K. Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem. 1994;63:345–382. doi: 10.1146/annurev.bi.63.070194.002021. [DOI] [PubMed] [Google Scholar]
  4. Geisler N., Kaufmann E., Weber K. Proteinchemical characterization of three structurally distinct domains along the protofilament unit of desmin 10 nm filaments. Cell. 1982 Aug;30(1):277–286. doi: 10.1016/0092-8674(82)90033-2. [DOI] [PubMed] [Google Scholar]
  5. Geisler N., Weber K. The amino acid sequence of chicken muscle desmin provides a common structural model for intermediate filament proteins. EMBO J. 1982;1(12):1649–1656. doi: 10.1002/j.1460-2075.1982.tb01368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goebel H. H. Desmin-related myopathies. Curr Opin Neurol. 1997 Oct;10(5):426–429. doi: 10.1097/00019052-199710000-00012. [DOI] [PubMed] [Google Scholar]
  7. Goebel H. H. Desmin-related neuromuscular disorders. Muscle Nerve. 1995 Nov;18(11):1306–1320. doi: 10.1002/mus.880181114. [DOI] [PubMed] [Google Scholar]
  8. Goebel H. H., Voit T., Warlo I., Jacobs K., Johannsen U., Müller C. R. Immunohistologic and electron microscopic abnormalities of desmin and dystrophin in familial cardiomyopathy and myopathy. Rev Neurol (Paris) 1994 Jun-Jul;150(6-7):452–459. [PubMed] [Google Scholar]
  9. Goldfarb L. G., Park K. Y., Cervenáková L., Gorokhova S., Lee H. S., Vasconcelos O., Nagle J. W., Semino-Mora C., Sivakumar K., Dalakas M. C. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet. 1998 Aug;19(4):402–403. doi: 10.1038/1300. [DOI] [PubMed] [Google Scholar]
  10. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  11. Lazarides E. Intermediate filaments as mechanical integrators of cellular space. Nature. 1980 Jan 17;283(5744):249–256. doi: 10.1038/283249a0. [DOI] [PubMed] [Google Scholar]
  12. Li D., Tapscoft T., Gonzalez O., Burch P. E., Quiñones M. A., Zoghbi W. A., Hill R., Bachinski L. L., Mann D. L., Roberts R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999 Aug 3;100(5):461–464. doi: 10.1161/01.cir.100.5.461. [DOI] [PubMed] [Google Scholar]
  13. Li Z. L., Lilienbaum A., Butler-Browne G., Paulin D. Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development. Gene. 1989 May 30;78(2):243–254. doi: 10.1016/0378-1119(89)90227-8. [DOI] [PubMed] [Google Scholar]
  14. Li Z., Colucci-Guyon E., Pinçon-Raymond M., Mericskay M., Pournin S., Paulin D., Babinet C. Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev Biol. 1996 May 1;175(2):362–366. doi: 10.1006/dbio.1996.0122. [DOI] [PubMed] [Google Scholar]
  15. Muñoz-Mármol A. M., Strasser G., Isamat M., Coulombe P. A., Yang Y., Roca X., Vela E., Mate J. L., Coll J., Fernández-Figueras M. T. A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11312–11317. doi: 10.1073/pnas.95.19.11312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nakai K., Sakamoto H. Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene. 1994 Apr 20;141(2):171–177. doi: 10.1016/0378-1119(94)90567-3. [DOI] [PubMed] [Google Scholar]
  17. Nakano S., Engel A. G., Waclawik A. J., Emslie-Smith A. M., Busis N. A. Myofibrillar myopathy with abnormal foci of desmin positivity. I. Light and electron microscopy analysis of 10 cases. J Neuropathol Exp Neurol. 1996 May;55(5):549–562. doi: 10.1097/00005072-199605000-00008. [DOI] [PubMed] [Google Scholar]
  18. Ohno K., Brengman J. M., Felice K. J., Cornblath D. R., Engel A. G. Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing? Am J Hum Genet. 1999 Sep;65(3):635–644. doi: 10.1086/302551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ohno Y., Sebetan I. M., Akaishi S. A simple method for calculating the probability of excluding paternity with any number of codominant alleles. Forensic Sci Int. 1982 Jan-Feb;19(1):93–98. doi: 10.1016/0379-0738(82)90155-4. [DOI] [PubMed] [Google Scholar]
  20. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  21. Porte A., Stoeckel M. E., Sacrez A., Batzenschlager A. Unusual familial cardiomyopathy with storage of intermediate filaments in the cardiac muscular cells. Virchows Arch A Pathol Anat Histol. 1980;386(1):43–58. doi: 10.1007/BF00432643. [DOI] [PubMed] [Google Scholar]
  22. Raats J. M., Henderik J. B., Verdijk M., van Oort F. L., Gerards W. L., Ramaekers F. C., Bloemendal H. Assembly of carboxy-terminally deleted desmin in vimentin-free cells. Eur J Cell Biol. 1991 Oct;56(1):84–103. [PubMed] [Google Scholar]
  23. Raats J. M., Schaart G., Henderik J. B., van der Kemp A., Dunia I., Benedetti E. L., Pieper F. R., Ramaekers F. C., Bloemendal H. Muscle-specific expression of a dominant negative desmin mutant in transgenic mice. Eur J Cell Biol. 1996 Nov;71(3):221–236. [PubMed] [Google Scholar]
  24. Shaw M. A., Atkinson S. E., Li Z., Paulin D., Blackwell J. M. EcoRV RFLP of the desmin (DES) gene and MspI RFLP of the villin (VIL1) gene on human chromosome 2. Hum Mol Genet. 1992 Sep;1(6):448–448. doi: 10.1093/hmg/1.6.448. [DOI] [PubMed] [Google Scholar]
  25. Sjöberg G., Saavedra-Matiz C. A., Rosen D. R., Wijsman E. M., Borg K., Horowitz S. H., Sejersen T. 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 Nov;8(12):2191–2198. doi: 10.1093/hmg/8.12.2191. [DOI] [PubMed] [Google Scholar]
  26. Thornell L., Carlsson L., Li Z., Mericskay M., Paulin D. Null mutation in the desmin gene gives rise to a cardiomyopathy. J Mol Cell Cardiol. 1997 Aug;29(8):2107–2124. doi: 10.1006/jmcc.1997.0446. [DOI] [PubMed] [Google Scholar]
  27. Vicart P., Dupret J. M., Hazan J., Li Z., Gyapay G., Krishnamoorthy R., Weissenbach J., Fardeau M., Paulin D. Human desmin gene: cDNA sequence, regional localization and exclusion of the locus in a familial desmin-related myopathy. Hum Genet. 1996 Oct;98(4):422–429. doi: 10.1007/s004390050233. [DOI] [PubMed] [Google Scholar]
  28. Viegas-Péquignot E., Li Z. L., Dutrillaux B., Apiou F., Paulin D. Assignment of human desmin gene to band 2q35 by nonradioactive in situ hybridization. Hum Genet. 1989 Aug;83(1):33–36. doi: 10.1007/BF00274143. [DOI] [PubMed] [Google Scholar]
  29. Yu K. R., Hijikata T., Lin Z. X., Sweeney H. L., Englander S. W., Holtzer H. Truncated desmin in PtK2 cells induces desmin-vimentin-cytokeratin coprecipitation, involution of intermediate filament networks, and nuclear fragmentation: a model for many degenerative diseases. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2497–2501. doi: 10.1073/pnas.91.7.2497. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES