Abstract
BackgroundLMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro.MethodsBetween January, 2008 and June, 2012 two patient populations were screened for the presence of LMNA mutations by direct sequencing: 66 dilated cardiomyopathy patients including 27 heart transplant recipients and 39 dilated cardiomyopathy patients with heart failure referred for heart transplantation evaluation, and 44 consecutive dilated cardiomyopathy patients, referred for a family evaluation and mutation screening.ResultsWe detected nine non-synonymous mutations including three novel mutations: p.Ser431*, p.Val256Gly and p.Gly400Argfs*11 deletion. There were 25 carriers altogether in nine families. The carriers were mostly characterized by dilated cardiomyopathy and heart failure with conduction system disease and/or complex ventricular arrhythmia, although five were asymptomatic. Among the LMNA mutation carriers, six underwent heart transplantation, fourteen ICD implantation and eight had pacemaker. In addition, we obtained ultrastructural images of cardiomyocytes from the patient carrying p.Thr510Tyrfs*42. Furthermore, because the novel p.Val256Gly mutation was found in a sporadic case, we verified its pathogenicity by expressing the mutation in a cellular model.ConclusionsIn conclusion, in the two referral centre populations, the screening revealed five mutations among 66 heart transplant recipients or patients referred for heart transplantation (7.6%) and four mutations among 44 consecutive dilated cardiomyopathy patients referred for familial evaluation (9.1%). Dilated cardiomyopathy patients with LMNA mutations have poor prognosis, however considerable clinical variability is present among family members.
Highlights
LMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease
The study comprised of two patient populations: heart transplant (HTx) recipients or patients referred for HTx evaluation and consecutive DCM patients referred for familial evaluation and mutation screening
The first cohort consisted of 66 DCM patients (61 men, mean age 42.2 ± 14 years) from the Outpatient Heart Failure Clinic (Warsaw, Poland) including 27 HTx recipients and 39 patients with DCM-related advanced heart failure (HF) referred for HTx
Summary
LMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro. Mutations in LMNA are among the most frequently detected mutations in DCM [3,4], especially in cases with conduction system disease [5]. DCM patients with LMNA mutations have poor prognosis with life-threatening ventricular arrhythmias, progression to heart failure and high risk of sudden cardiac death (SCD) [6,7]. In 2005, a Canadian-Irish-Polish joint study demonstrated LMNA mutations in 4.4% of consecutive DCM cases [8]. In order to extend these observations, we embarked on another study to identify LMNA mutations, estimate their frequency among DCM patients and characterize their effect. The study comprised of two patient populations: heart transplant (HTx) recipients or patients referred for HTx evaluation and consecutive DCM patients referred for familial evaluation and mutation screening
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