title: Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations.
abstract: OBJECTIVE
  Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms.
  
  
  METHODS
  We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified.
  
  
  RESULTS
  A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H).
  
  
  CONCLUSIONS
  For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.
authors.affiliation: Laboratoire Génétique et Insuffisance Cardiaque, Association Claude Bernard/Université Paris VI, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. sebilion@infobiogen.fr
authors.forename: P
authors.initials: P
authors.lastname: Sébillon
authors.forename: C
authors.initials: C
authors.lastname: Bouchier
authors.forename: L D
authors.initials: LD
authors.lastname: Bidot
authors.forename: G
authors.initials: G
authors.lastname: Bonne
authors.forename: K
authors.initials: K
authors.lastname: Ahamed
authors.forename: P
authors.initials: P
authors.lastname: Charron
authors.forename: V
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: A
authors.initials: A
authors.lastname: Millaire
authors.forename: G
authors.initials: G
authors.lastname: Desrumeaux
authors.forename: A
authors.initials: A
authors.lastname: Benaïche
authors.forename: J-C
authors.initials: JC
authors.lastname: Charniot
authors.forename: K
authors.initials: K
authors.lastname: Schwartz
authors.forename: E
authors.initials: E
authors.lastname: Villard
authors.forename: M
authors.initials: M
authors.lastname: Komajda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D002460:Cell Line; D002648:Child; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D032446:Myoblasts / Q000737:chemistry / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014162:Transfection
chemical_list: D034904:Lamin Type A