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J Med Genet 42:639-647 doi:10.1136/jmg.2004.023283
  • Original article

In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients

  1. N Sylvius1,
  2. Z T Bilinska2,
  3. J P Veinot3,
  4. A Fidzianska4,
  5. P M Bolongo1,
  6. S Poon1,
  7. P McKeown5,
  8. R A Davies6,
  9. K-L Chan6,
  10. A S L Tang6,
  11. S Dyack7,
  12. J Grzybowski2,
  13. W Ruzyllo2,
  14. H McBride8,
  15. F Tesson1
  1. 1Laboratory of Genetics of Cardiac Diseases, University of Ottawa Heart Institute, Ottawa, ON, Canada
  2. 2National Institute of Cardiology, Warsaw, Poland
  3. 3Department of Pathology and Laboratory Medicine, University of Ottawa, Anatomical Pathology, Ottawa Hospital, Ottawa, ON, Canada
  4. 4Polish Academy of Sciences, Warsaw, Poland
  5. 5Department of Medicine, Queen’s University of Belfast, Belfast, UK
  6. 6Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada
  7. 7Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
  8. 8Lipoproteins and Atherosclerosis Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada
  1. Correspondence to:
 Dr F Tesson
 University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada; ftessonottawaheart.ca
  • Received 26 May 2004
  • Accepted 4 February 2005
  • Revised 31 January 2005

Abstract

Context: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood.

Methods and results: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern.

Conclusion: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.

Footnotes

  • This research was supported by Canadian Institutes for Health Research operating grants 38054 and 65152, and by Heart and Stroke Foundation grant NA 5101 awarded to F Tesson. Polish patients and families were studied with support of grant no. 0010/P05B/98/14 from the Polish Committee for Scientific Research. N Sylvius is the recipient of the fellowship awarded by the Heart and Stroke Foundation of Ontario Program grant 5275.

  • Competing interests: none declared