Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy

PLoS One. 2015 Apr 2;10(4):e0121723. doi: 10.1371/journal.pone.0121723. eCollection 2015.


Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Amino Acid Sequence
  • Apoptosis / genetics
  • Arrhythmias, Cardiac / complications
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmogenic Right Ventricular Dysplasia / complications
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Arrhythmogenic Right Ventricular Dysplasia / pathology
  • Arrhythmogenic Right Ventricular Dysplasia / physiopathology
  • Brugada Syndrome
  • Cardiac Conduction System Disease
  • Cardiomyopathy, Dilated / complications
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology
  • Case-Control Studies
  • Death, Sudden, Cardiac / etiology
  • Death, Sudden, Cardiac / pathology
  • Exons
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heart Conduction System / abnormalities*
  • Heart Conduction System / pathology
  • Heart Conduction System / physiopathology
  • Heterozygote
  • Humans
  • Lamin Type A / genetics*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Pedigree
  • Penetrance
  • Primary Cell Culture
  • Sequence Alignment


  • LMNA protein, human
  • Lamin Type A

Grants and funding

This work was supported by the Italian Ministry of University, Scientific and Technical Research (grant number ORBA1085M0 to SF), and by Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica (grant number RBRN07BMCT_009 to MS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.