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Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy

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Abstract

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%–50% of DCM cases. It is a heterogenous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most inportant disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.

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Acknowledgments

We are grateful to the patients and their relatives for their participation in the study. The Berlin Institute for Heart Research (BIHR) and the Deutsche Herzstiftung supported this study. Further, this work was supported by the Competence Network of Heart Failure funded by the Federal Ministry of Education and Research (BMBF), FKZ 01GI0205. The support of N.T.D. by the Joint Graduate Education Program of Deutscher Akademischer Austauschdienst (DAAD, VNM 04/A17) is acknowledged as well as the support of M.S.W. by a grant of the BMBF (01GM0302).

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Authors and Affiliations

  1. Charité–Universitätsmedizin Berlin, Kardiologie am Campus Buch und Virchow-Klinikum, Experimental and Clinical Research Center (ECRC) am Max-Delbrück-Centrum für Molekulare Medizin, Lindenberger Weg 80, 13125, Berlin, Germany

    Andreas Perrot, Shwan Hussein, Maximilian G. Posch, Anna Panek, Rainer Dietz & Cemil Özcelik

  2. Klinik für Kardiologie, Universitätsklinikum Gießen und Marburg GmbH, Marburg, Germany

    Volker Ruppert, Anette Richter, Bernhard Maisch & Sabine Pankuweit

  3. Transplantationshepatologie, Universitätsklinikum Münster, Münster, Germany

    Hartmut H. J. Schmidt

  4. Institut für Humangenetik, Ernst Moritz Arndt Universität Greifswald, Greifswald, Germany

    Manfred S. Wehnert & Nguyen Thuy Duong

  5. Klinik für Innere Medizin III/Kardiologie and Angiologie, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

    Ingrid Kindermann & Michael Böhm

  6. 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland

    Aleksandra Michalewska-Wludarczyk

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  1. Andreas Perrot
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Correspondence to Andreas Perrot.

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Returned for 1. Revision: 18 February 2008 1. Revision received: 12 August 2008 Returned for 2. Revision: 20 August 2008 2. Revision received: 21 August 2008

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Perrot, A., Hussein, S., Ruppert, V. et al. Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. Basic Res Cardiol 104, 90–99 (2009). https://doi.org/10.1007/s00395-008-0748-6

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