title: Dilated cardiomyopathy caused by LMNA mutations. Clinical and morphological studies.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is familial in about 20-35% of patients. The most frequently encountered mutations associated with DCM are found in LMNA.
  
  
  OBJECTIVE
  To define the frequency of LMNA mutations in a series of consecutive DCM patients and to evaluate the phenotype of mutation carriers.
  
  
  METHODS
  We screened the 12 exons of LMNA in a series of 61 Polish patients with DCM diagnosed angiographically, as well as in two DCM families.
  
  
  RESULTS
  Two mutations were detected in 5 mutation carriers (D192G in one proband and Y481Stop in one proband and 3 of his offspring), which represents 3.3% (2/61) of the DCM patients. These mutations were absent from 100 controls. The D192G mutation was found in a 26-year-old patient with mild DCM and heart failure leading to death within two years after onset of symptoms. Mild conduction disease was also present. Ultrastructural analysis of the endomyocardial biopsy showed a striking alteration of nuclear morphology. This finding can explain nuclear fragility and is in agreement with the pathophysiological mechanical hypothesis of LMNA mutations. All four Y481Stop mutation-carriers were affected. Three phenotypes were found: in the proband, cardiac dysrhythmia and pacemaker requirement preceded DCM leading to heart transplantation; the proband's 13-year old daughter had conduction disease (2nd degree A-V block) with subtle skeletal muscle involvement documented by immunofluorescence study; ventricular arrhythmia was detected in the proband's son at the age of 11 and in the proband's daughter at the age of 18. Serum creatine kinase was normal in all mutation carriers.
authors.affiliation: Instytut Kardiologii ul. Alpejska 42, 04-628 Warsaw, Poland. zbilinska@ikard.pl
authors.forename: Zofia T
authors.initials: ZT
authors.lastname: Bilińska
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sylvius
authors.forename: Jacek
authors.initials: J
authors.lastname: Grzybowski
authors.forename: Anna
authors.initials: A
authors.lastname: Fidziańska
authors.forename: Ewa
authors.initials: E
authors.lastname: Michalak
authors.forename: Ewa
authors.initials: E
authors.lastname: Walczak
authors.forename: Michał
authors.initials: M
authors.lastname: Walski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bieganowska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Szymaniak
authors.forename: Beata
authors.initials: B
authors.lastname: Kuśmierczyk-Droszcz
authors.forename: Barbara
authors.initials: B
authors.lastname: Lubiszewska
authors.forename: Teresa
authors.initials: T
authors.lastname: Wagner
authors.forename: Frederique
authors.initials: F
authors.lastname: Tesson
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyłło
mesh_terms: D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D034904:Lamin Type A; D034882:Lamins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure*; D034881:Nuclear Lamina / Q000235:genetics* / Q000648:ultrastructure*; D010375:Pedigree; D011237:Predictive Value of Tests; D015995:Prevalence; D018709:Statistics, Nonparametric
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D034882:Lamins