Abstract
Background and Objective: Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation.
Methods: A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing.
Results: We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing.
Conclusion: LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.
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Acknowledgments
This work was supported by a Polish State Committee for Scientific Research and Institute of Cardiology grant (registration no. 2.20/II/08; source of funding for M. Saj, R. Dabrowski, M. Szperl, G. Broda, H. Szwed, Z.T. Bilinska, and R. Ploski), a Heart and Stroke Foundation grant (no. NA 6628, awarded to F. Tesson; source of funding for S. Labib and F. Tesson), a National Science Centre (NCN) grant (no. 2011/01/B/NZ4/03455), and a Medical University of Warsaw grant (no. 1WY/W1/10; source of funding for R. Ploski). These grants covered all processes that resulted in the submission of this manuscript.
The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and the current ethical laws of Poland and Canada. The authors declare that they have no conflict of interest.
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Saj, M., Dabrowski, R., Labib, S. et al. Variants of the Lamin A/C (LMNA) Gene in Non-Valvular Atrial Fibrillation Patients. Mol Diagn Ther 16, 99–107 (2012). https://doi.org/10.1007/BF03256434
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DOI: https://doi.org/10.1007/BF03256434