Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) can be caused by mutations in genes encoding for the ventricular myosin essential and regulatory light chains. In contrast to other HCM disease genes, only a few studies describing disease-associated mutations in the myosin light chain genes have been published. Therefore, we aimed to conduct a systematic screening for mutations in the ventricular myosin light chain genes in a group of clinically well-characterised HCM patients. Further, we assessed whether the detected mutations are associated with malignant or benign phenotype in the respective families. We analysed 186 unrelated individuals with HCM for the human ventricular myosin regulatory (MYL2) and essential light chain genes (MYL3) using polymerase chain reaction, single strand conformation polymorphism analysis and automated sequencing. We found eight single nucleotide polymorphisms in exonic and adjacent intronic regions of MYL2 and MYL3. Two MYL2 missense mutations were identified in two Caucasian families while no mutation was found in MYL3. The mutation Glu22Lys was associated with moderate septal hypertrophy, a late onset of clinical manifestation, and benign disease course and prognosis. The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death. In conclusion, myosin light chain mutations are a very rare cause of HCM responsible for about 1% of cases. Mutations in MYL2 could be associated with both benign and malignant HCM phenotype.

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

“…Thus, a mixture of two myosin species having substantially different mechanical capacities can lead to internal stress within the muscle cell, which in turn can result in cellular disarray for the occurrence of HF or sudden death. In patients with rare defects of MLC 1 , MLC 2 and α-TM genes, the mutations induce an increase in Ca 2+ sensitivity and force production (174,(189)(190)(191), leading to hypercontractile myocardium. Increased expression of ALC 1 was observed in the ventricles of patients suffering from fHCM, partially replacing the ventricular isoform VLC 1 .…”

The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice

“…Recent studies have revealed that the ventricular isoform of myosin regulatory light-chain [RLC; also known as myosin regulatory light-chain 2 (MLRV)] is one of the sarcomeric proteins associated with FHC (Andersen et al, 2001;Flavigny et al, 1998;Kabaeva et al, 2002;Poetter et al, 1996;Richard et al, 2003) (Z. T. Kabaeva, Genetic analysis in hypertrophic cardiomyopathy: missense mutations in the ventricular myosin regulatory light chain gene, PhD thesis, Humboldt Universitat zu Berlin, 2002). The clinical course of FHC is variable and ranges from benign to severe heart failure and sudden cardiac death.…”

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

“…Multiple reports of MYL2 genetic variations have been published to date. They are A13T (Andersen et al 2001;Hougs et al 2005;Poetter et al 1996), F18L (Flavigny et al 1998;Richard et al 2003), M20L (Olivotto et al 2008), E22K (Garcia-Pavia et al 2011;Kabaeva et al 2002;Poetter et al 1996); I44M (Santos et al 2012), N47K (Andersen et al 2001), G57E (Caleshu et al 2011, R58Q (Flavigny et al 1998;Kabaeva et al 2002;Morner et al 2003;Olivotto et al 2008;Richard et al 2003), P95A (Poetter et al 1996), K104E (Andersen et al 2001), E134A (Di Donna et al 2010;Olivotto et al 2008); D166V, IVS5-2 (an A > G transversion in intron 5 that leads to a premature termination codon) , and IVS6-1 (a G > C transversion in the acceptor splice site of intron 6) (Andersen et al 2001). Recently, a novel sarcomeric protein mutation in the MYL2 gene was identified by exome sequencing in a pedigree with familial dilated cardiomyopathy (DCM) .…”