LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies

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.

The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation

“…The prevalence of BAG3 defects in our cohort was relatively high (6/90 or 6.7%) being comparable to the prevalence of mutations in LMNA (~6%) which has been regarded as the most frequently mutated locus in DCM [23,24]. Thus, the BAG3 gene emerges as a major DCM locus.…”

Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene

“…First, our pedigree analysis indicated that while the LMNA -related cardiac disease was introduced into the family by the maternal grandfather (II-7), DD was introduced by the proband’s maternal grandmother (II-8), the only DD-affected individual with no cardiac disease. Furthermore, patients previously reported to carry the same nonsense mutation as our family, or other premature truncation mutations with mechanisms consistent with Lamin A/C haploinsufficiency, did not have DD or LD [ 21 , 24 , 25 , 27 ]. LMNA c.736C>T (p.Gln246Stop) has been previously described in two families with DCM and atrioventricular block that includes an Italian proband [ 24 ] and a Polish 40-year-old male proband with a family history of heart failure [ 25 ]; however, extra-cardiac features were not reported.…”

“…Furthermore, patients previously reported to carry the same nonsense mutation as our family, or other premature truncation mutations with mechanisms consistent with Lamin A/C haploinsufficiency, did not have DD or LD [ 21 , 24 , 25 , 27 ]. LMNA c.736C>T (p.Gln246Stop) has been previously described in two families with DCM and atrioventricular block that includes an Italian proband [ 24 ] and a Polish 40-year-old male proband with a family history of heart failure [ 25 ]; however, extra-cardiac features were not reported. These observations suggest that DD is not exclusive to laminopathy patients and additional genetics factors in family members heterozygous for the LMNA mutation may increase the susceptibility to develop DD along with the primary laminopathy phenotype of cardiac disease.…”

“…We report LMNA c.736C>T (p.Gln246Stop), a previously described nonsense mutation as the primary mutation in a family with typical LMNA -related cardiac disease that includes DCM, cardiac conduction defects, and sudden death [ 24 , 25 , 26 ]. To investigate the molecular mechanism by which LMNA c.736C>T (p.Gln246Stop) may lead to disease, we conducted RNA studies on patient and control fibroblasts.…”

Successful cardiac transplantation in a patient with congenital generalized lipodystrophy

“…Successful renal transplantation in a patient with congenital generalized lipodystrophy was reported 12 yr ago . However, few unsuccessful renal transplantation cases in patients with different types of lipodystrophy had been also communicated before leptin and the advent of modern lipid‐lowering therapeutics . In our case, metabolic control was achieved with patient‐specific immunosuppressive therapy modification and resuming leptin dose.…”