title: Variants of the lamin A/C (LMNA) gene in non-valvular atrial fibrillation patients: a possible pathogenic role of the Thr528Met mutation.
abstract: OBJECTIVE
  Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation.
  
  
  METHODS
  A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing.
  
  
  RESULTS
  We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing.
  
  
  CONCLUSIONS
  LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.
authors.affiliation: Laboratory of Molecular Biology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Saj
authors.forename: Rafal
authors.initials: R
authors.lastname: Dabrowski
authors.forename: Sarah
authors.initials: S
authors.lastname: Labib
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jankowska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szperl
authors.forename: Grazyna
authors.initials: G
authors.lastname: Broda
authors.forename: Hanna
authors.initials: H
authors.lastname: Szwed
authors.forename: Frederique
authors.initials: F
authors.lastname: Tesson
authors.forename: Zofia T
authors.initials: ZT
authors.lastname: Bilinska
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A