Functional consequences of anLMNAmutation associated with a new cardiac and non-cardiac phenotype

Abstract

Heritable dilated cardiomyopathy is a genetically highly heterogeneous disease. To date 17 different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy with or without additional clinical manifestations. Among the 10 mutated genes associated with dilated cardiomyopathy, the lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy. For the first time, we report here a French family affected with a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias, and a specific quadriceps muscle myopathy. In all previously reported cases with both cardiac and neuromuscular involvement, neuromuscular disorders preceded cardiac abnormalities. The screening of the coding sequence of the LMNA gene on all family members was performed and we identified a missense mutation (R377H) in the lamin A/C gene that cosegregated with the disease in the family. Cell transfection experiments showed that the R377H mutation leads to mislocalization of both lamin and emerin. These results were obtained in both muscular (C2C12) and non-muscular cells (COS-7). This new phenotype points out the wide spectrum of neuromuscular and cardiac manifestations associated with lamin A/C mutations, with the functional consequence of this mutation seemingly associated with a disorganization of the lamina.

<i>LMNA</i> Mutations in Cardiac Transplant Recipients

“…Histological examination confirmed cardiomyopathy, but did not reveal any specific pattern for LMNA mutant carriers. However, immunohistochemistry has been shown to detect altered lamin A/C expression in patients carrying LMNA mutations [41], which is similar to the in vitro observations in transfected cells [42]. At this point, there is not enough information available to speculate on any genotype/phenotype correlation.…”

Severe Myocardial Fibrosis Caused by a Deletion of the 5’ End of the Lamin A/C Gene

“…The exact pathophysiological mechanism of LMNA mutations that lead to such an impressive heterogeneous spectrum of disorders has not yet been elucidated. However, myocardial fibrosis as a secondary phenomenon has been described before in different laminopathies (10,15,33). The identified deletion of the 5' end of the LMNA gene containing the start codon is predicted to affect mainly the head domain of lamin (that is, it might lead to a shortened protein lacking the head domain).…”

Clinical and genetic heterogeneity in laminopathies

“…The only relationship that has emerged so far has been reported by Benedetti et al [32], who showed that patients with early skeletal muscle involvement carry essentially missense mutations, whereas patients presenting with a later onset of their muscle symptoms carried frameshift mutations, presumably leading to truncated proteins. However, the same mutation within a single family can give rise to variable phenotypes [14,15,[33][34][35][36][37][38], suggesting that, besides LMNA mutation, additional players are involved to account for this variability. Among these players, digenism has been reported in a few cases that may explain in part this variability.…”