Elsevier

Heart Rhythm

Volume 6, Issue 5, May 2009, Pages 707-710
Heart Rhythm

Case report
A novel mutation in LAMIN A/C is associated with isolated early-onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac death

https://doi.org/10.1016/j.hrthm.2009.01.037Get rights and content

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults requiring hospitalization and is characterized by rapid and irregular activation of the atria. Loss of effective atrial contraction leads to decreased ventricular filling and cardiac output, whereas stasis of blood in the atria increases the risk for thromboembolic stroke.1 Although most AF develops as a consequence of other systemic processes, such as hypertensive, valvular, or coronary artery disease, 10% to 20% occurs in individuals without underlying risk factors. Genetic factors are implicated in the development of isolated AF, with nearly 40% of cases having a positive family history.2, 3 Disease-causing mutations have been found in cardiac potassium channel genes, although mutations in sodium channels and connexins have also been implicated.4 An infrequent genetic etiology is mutation in the gene encoding for lamin A/C, LMNA, but the AF is typically associated with a combined cardiac and skeletal myopathy.5

The LMNA gene resides on chromosome 1q21 and it encodes for 2 isoforms, lamin A and C, which are generated by alternative splicing (Figure 1D). Lamins A and C are intermediate-filament proteins that form the nuclear lamina, function as a nuclear scaffold to maintain the structure and size of the nucleus, and are also implicated in transcriptional regulation, nuclear pore positioning, and heterochromatin organization.6 Mutations in nuclear lamins and lamin-associated proteins cause more than 16 distinct human diseases, termed laminopathies. Lamin A/C is expressed in multiple cell types, and mutations in LMNA result in a range of phenotypes, including premature aging syndromes, types of muscular dystrophy, a subset of lipodystrophies, bone dysplasias, and cardiovascular diseases.7 The cardiac involvement in laminopathies usually presents with progressive atrioventricular block (AVB), dilated cardiomyopathy (DCM), sudden cardiac death (SCD), and infrequently, atrial arrhythmias. It remains unknown how mutations in these ubiquitously expressed proteins cause such heterogeneous phenotypes with variable penetrance.

We present a large family in which a novel mutation of LMNA segregates with affected members with cardiac disease. The phenotype consists of early-onset AF and progressive AVB that is followed by DCM and SCD. In this article, we discuss the clinical and genetic findings and emphasize that LMNA mutations are a potential cause of early-onset AF and progressive conduction system disease.

Section snippets

Case report

We identified a family of Han Chinese ancestry spanning 3 generations with autosomal-dominant cardiac disease that had 15 affected members (Figure 1A). The disease was 100% penetrant in family members over 40 years of age, and no members showed muscular dystrophy or other organ system involvement, as commonly described in other laminopathies.7 Clinical histories are summarized in Figure 1B and were obtained by review of available medical records, detailed family histories, and a previous case

Discussion

This family exemplifies the progressive nature of conduction system disease in subjects who harbor mutations in LMNA. Conduction abnormalities have long been recognized as a component of cardiac laminopathies since the first description of a large family with autosomal dominant Emery-Dreifuss muscular dystrophy, which is characterized by a skeletal and cardiac myopathy along with progressive heart block.11 Subsequently, mutations in LMNA were identified in individuals with isolated cardiac

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Dr. Yin is supported by grants from the National Institutes of Health/National Institute of General Medical Sciences and The Welch Foundation. Dr. Garg is supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and the March of Dimes Birth Defects Association.

The authors thank family members for their participation; S. Tsai and T. Hyatt in the McDermott Center for Human Growth and Development for technical support; J. Chen for translation of medical records; M. Maitra and H. Hsia for helpful discussions; and P. J. Kannankeril for review of the manuscript.

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