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Functional consequences of an LMNA mutation associated with a new cardiac and non‐cardiac phenotype
Author(s) -
Charniot JeanChristophe,
Pascal Cécile,
Bouchier Christiane,
Sébillon Pascale,
Salama Jeffrey,
DuboscqBidot Laëtitia,
Peuchmaurd Mireille,
Desnos Michel,
Artigou JeanYves,
Komajda Michel
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10170
Subject(s) - lmna , lamin , dilated cardiomyopathy , missense mutation , biology , cardiomyopathy , genetics , myopathy , mutation , phenotype , muscular dystrophy , neuromuscular disease , medicine , gene , heart failure , disease
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. Hum Mutat 21:473–481, 2003. © 2003 Wiley‐Liss, Inc.