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Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption

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Abstract

Major nuclear envelope abnormalities, such as disruption and/or presence of intranuclear organelles, have rarely been described in cardiomyocytes from dilated cardiomyopathy (DCM) patients. In this study, we screened a series of 25 unrelated DCM patient samples for (a) cardiomyocyte nuclear abnormalities and (b) mutations in LMNA and TMPO as they are two DCM-causing genes that encode proteins involved in maintaining nuclear envelope architecture. Among the 25 heart samples investigated, we identified major cardiomyocyte nuclear abnormalities in 8 patients. Direct sequencing allowed the detection of three heterozygous LMNA mutations (p.D192G, p.Q353K and p.R541S) in three patients. By multiplex ligation-dependant probe amplification (MLPA)/quantitative real-time PCR, we found a heterozygous deletion encompassing exons 3–12 of the LMNA gene in one patient. Immunostaining demonstrated that this deletion led to a decrease in lamin A/C expression in cardiomyocytes from this patient. This LMNA deletion as well as the p.D192G mutation was found in patients displaying major cardiomyocyte nuclear envelope abnormalities, while the p.Q353K and p.R541S mutations were found in patients without specific nuclear envelope abnormalities. None of the DCM patients included in the study carried a mutation in the TMPO gene. Taken together, we found no evidence of a genotype–phenotype relationship between the onset and the severity of DCM, the presence of nuclear abnormalities and the presence or absence of LMNA mutations. We demonstrated that a large deletion in LMNA associated with reduced levels of the protein in the nuclear envelope suggesting a haploinsufficiency mechanism can lead to cardiomyocyte nuclear envelope disruption and thus underlie the pathogenesis of DCM.

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Acknowledgments

The work was supported by Canadian Institutes for Health Research operating grants 38054, 65152 and 77685, and by Heart and Stroke Foundation Grants NA 5101 and 6628 awarded to F. Tesson and by an internal grant from the Institute of Cardiology (Warsaw, Poland) no:2.57/VII/03. At the time the study was conducted, N. Sylvius was the recipient of the fellowships awarded by the Heart and Stroke Foundation of Ontario Program Grant 5275 and Astra Zeneca/Canadian Society of Hypertension/CIHR, and Pallavi Gupta was the recipient of Ontario Graduate Scholarship in Science and Technology (OGSST). We acknowledge the important contribution of the Canadian Cardiovascular Genetics Centre (Ottawa, Canada).

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The authors declare that they have no conflict of interest.

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  1. Nicolas Sylvius

    Present address: Department of Biochemistry, University of Leicester, Leicester, LE1 9HN, UK

Authors and Affiliations

  1. Faculty of Health Sciences, University of Ottawa, 451 Smyth, Ottawa, ON, K1H 8M5, Canada

    Pallavi Gupta, Nicolas Sylvius, Emilie Boudreau, Sarah Labib, Pierrette M. Bolongo, Akil Hamza, Tracy Jackson & Frédérique Tesson

  2. 1st Department of Coronary Artery Disease, Institute of Cardiology, Alpejska 42, 04-6 28, Warsaw, Poland

    Zofia T. Bilinska & Jacek Grzybowski

  3. Department of Pathology and Laboratory Medicine, University of Ottawa, Anatomical Pathology, Ottawa Hospital, Ottawa, ON, K1Y 4E9, Canada

    John P. Veinot

  4. Department of Medical Genetics, Warsaw Medical University, Pawinskiego Street 3c, 02-106, Warsaw, Poland

    Rafal Ploski

  5. Department of Cell Ultrastructure, M Mossakowski Medical Research Centre, Polish Academy of Science, Pawinskiego Street 5, 02-106, Warsaw, Poland

    Michal Walski

  6. Department of Pathology, Institute of Rheumatology, Spartanska 1, 02-637, Warsaw, Poland

    Ewa Walczak

  7. 2nd Department of Cardiac Surgery, Institute of Cardiology, Alpejska 42, 04-628, Warsaw, Poland

    Grzegorz Religa

  8. Neuromuscular Unit, Medical Research Center, Polish Academy of Science, ul.Pawińskiego 5, 02-097, Warsaw, Poland

    Anna Fidzianska

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Gupta, P., Bilinska, Z.T., Sylvius, N. et al. Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption. Basic Res Cardiol 105, 365–377 (2010). https://doi.org/10.1007/s00395-010-0085-4

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