Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy

Abstract

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

“…All affected family members were shown to have the variant LMNA:c.656A4C, which has been previously demonstrated in an unrelated 43-year-old man with DCM. 17 In addition, the four most severely affected family members were found to have a previously not described variant in the gene for titin, TTN:c.14563C4T (p L4855F). Doubly heterozygous family members showed a substantially more severe clinical course, with respect to age of terminal CHF and heart transplantation, and a number of cardiological and histological LMNA/TTN mutations in severe DCMparameters (Figures 2 and 3).…”

“…individual with DCM, 17 and a previously unreported variant was found in the gene for titin (TTN:c.14563C4T; p.L4855F). There were no other variants in genes associated with cardiological phenotypes.…”

Lamin A/C mutations in dilated cardiomyopathy

“…Moreover, this apoptotic effect could be attenuated by pharmacological blockade of the MEK1/ERK1/2 pathway. Study of gene expression profile showed that mouse models of laminopathies also displayed ERK pathway activation in heart muscle [43,44]. Importantly, the pharmacological blockade of the ERK1/2 pathway prevented the development of DCM in this model [45].…”

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

“…Interestingly, both non-conserved residues are mutated to a proline and located adjacent to pathogenic residues. These are p.R190, associated with DCM when mutated to Trp or Gln (Perrot, et al, 2009;Sylvius, et al, 2005), and p.Y267, associated with EDMD and DCM when mutated to His or Cys (Carboni, et al, 2008;Vytopil, et al, 2003). Proline is not found in the centre of a straight alpha-helix, due to its helix breaking attributes (Richardson and Richardson, 1988).…”