title: Functional consequences of an LMNA mutation 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.
authors.affiliation: Service de Cardiologie, Avicenne Hospital, Bobigny, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Charniot
authors.forename: Cécile
authors.initials: C
authors.lastname: Pascal
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.forename: Pascale
authors.initials: P
authors.lastname: Sébillon
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Salama
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Duboscq-Bidot
authors.forename: Mireille
authors.initials: M
authors.lastname: Peuchmaurd
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Artigou
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D003893:Desmin / Q000032:analysis; D016189:Dystrophin / Q000032:analysis; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000032:analysis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins; D010375:Pedigree; D010957:Plasmids / Q000187:drug effects; D013946:Thymopoietins / Q000032:analysis; D014162:Transfection
chemical_list: D003893:Desmin; D016189:Dystrophin; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D013946:Thymopoietins; C092710:emerin; D004247:DNA