| *160781 | ||||||||||||||||||||||||||||||
| MYOSIN, LIGHT CHAIN 2, REGULATORY, CARDIAC, SLOW; MYL2 | ||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||
| MLC2 REGULATORY LIGHT CHAIN OF MYOSIN RLC OF MYOSIN MYOSIN, LIGHT CHAIN, REGULATORY VENTRICULAR | ||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: MYL2 | ||||||||||||||||||||||||||||||
| Cytogenetic location: 12q24.11 Genomic coordinates (GRCh37): 12:111,348,622 - 111,358,403 (from NCBI) | ||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||
| The 2 pairs of light chains of muscle myosins are called essential light chains (ELC) and regulatory light chains (RLC) (summarized by Poetter et al., 1996). The light chains stabilize the long alpha helical neck of the myosin head. Myosin light chain-2 (MYL2) is an important protein in the regulation of myosin ATPase activity in smooth muscle (summarized by Macera et al., 1992). An increase in ventricular MYL2 is observed in the hypertrophied myocardium of cardiac patients with valvular stenosis. | ||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||
| Libera et al. (1989) cloned full-length MYL2, which they called HVLC2, from a ventricle cDNA library. The deduced protein contains 165 amino acids. Using rat Myl2 to screen ventricle poly(A) RNA, Wadgaonkar et al. (1993) cloned human MYL2. The deduced 166-amino acid protein shares 96% homology with rat Myl2. Both proteins contain 2 N-terminal putative phosphorylation sites, an EF-hand domain with a central calcium-binding region, and a putative C-terminal myosin heavy chain (MHC; see 160710)-binding domain. They are clearly different from mammalian or avian skeletal and smooth muscle myosin light chains, particularly in the C-terminal domain. | ||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||
| Using a cloned cDNA for human MYL2, Macera et al. (1992) mapped the MYL2 gene to chromosome 12 by Southern blot analysis of DNA from human/rodent somatic cell hybrids. By in situ hybridization, they regionalized the gene to 12q23-q24.3. In a large family with hypertrophic cardiomyopathy due to mutation in the MYL2 gene (608758), Flavigny et al. (1998) performed haplotype analysis using 6 microsatellite markers and refined the interval containing the gene to a 6-cM region between D12S84 and D12S354. | ||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||
| Wadgaonkar et al. (1993) demonstrated that recombinant human ventricle MYL2 bound specifically to MHC. Recombinant MYL2 exchanged with native MYL2 in intact isolated myofibrils derived from cardiac and skeletal muscle. Fluorescence-labeled MYL2 stained the A band, with strongest staining of A-band edges. There was no staining of either I or Z bands. Domain analysis indicated that a central conserved domain of 20 amino acids recognized MHC. In human, mouse, and rabbit cardiac tissue, Davis et al. (2001) identified a spatial gradient from high (epicardial) to low (endocardial) levels of phosphorylated myosin RLC that correlated with levels of myosin light chain kinase-2 (MYLK2; 606566). Mechanical studies of single slow muscle fibers showed that the spatial gradient of RLC phosphorylation increased tension, decreased the stretch activation response of the epicardial fibers, and produced the converse effect in the endocardium. | ||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||
| Poetter et al. (1996) analyzed the MYL2 gene in 399 unrelated probands with hypertrophic cardiomyopathy (see CMH10, 608758), and identified heterozygosity for 3 different missense mutations in 4 probands (160781.0001-160781.0003), 3 of whom had an unusual mid-left ventricular chamber thickening on echocardiography. Poetter et al. (1996) also identified heterozygous missense mutations in the MYL3 gene (160790) in CMH patients (see CMH8, 608751), some of whom displayed similar mid-left ventricular chamber hypertrophy. Flavigny et al. (1998) screened 42 probands from unrelated families with CMH for mutations in the MYL2 gene and identified 2 novel mutations, R58Q (160781.0004) and P18L (160781.0005), in 3 probands. The mutations were subsequently found in all affected family members, who were classified morphologically as Maron type 1, 2, or 3; none had the variant form of CMH described by Poetter et al. (1996). Szczesna et al. (2001) studied the effects of 5 mutations in the MYL2 gene on Ca(2+) binding and phosphorylation and found that both processes were significantly affected by all of the mutations. For example, the E22K mutation resulted in a 17-fold decrease in calcium binding compared with wildtype, and the R58Q mutant did not bind Ca(2+) at all. Ca(2+) binding to the R58Q mutant was restored upon phosphorylation, whereas the E22K mutant could not be phosphorylated. In addition, the alpha-helical content of phosphorylated R58Q greatly increased with Ca(2+) binding. Kabaeva et al. (2002) analyzed the MYL2 and MYL3 genes in 186 unrelated individuals with CMH and identified 2 missense mutations in MYL2: E22K and R58Q. The former was associated with a more benign phenotype and the latter with a more severe one of asymmetric septal hypertrophic cardiomyopathy. Grey et al. (2005) engineered embryonic stem cell lines to express wildtype or R58Q (160781.0004)-mutant MYL2, which differentiated into cardiomyocytes within embryoid bodies. Immunofluorescence studies revealed that mutated MYL2 dramatically prevented myofibrillogenesis, and cardiomyocytes expressing mutant MYL2 showed inhibited spontaneous Ca(2+) spiking and reduced translocation of MEF2C (600662) into the nucleus, which is a Ca(2+)-dependent process. Expression in mutated cells of a constitutively active CAMK2A (114078) or ionomycin treatment restored translocation of MEF2C into the nucleus, and expression of mRNAs encoding sarcomeric proteins partially rescued contractile activity of embryonic bodies. Grey et al. (2005) concluded that alteration of Ca(2+) homeostasis in mutated cardioblasts affects the transcriptional program of cardiac cell differentiation, leading to a defect in myofibrillogenesis and in contractility. | ||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||
| By creating transgenic mice overexpressing human MYL2 with the glu22-to-lys mutation (E22K; 160781.0002), Szczesna-Cordary et al. (2005) recapitulated the familial hypertrophic cardiomyopathy phenotype. Transgenic mice showed enlarged interventricular septa and papillary muscles, but no cardiac hypertrophy was found by echocardiography or by judging heart weight to body weight ratios. The E22K mutation increased calcium sensitivity of myofibrillar ATPase and steady-state force development in mutant cardiac muscle. | ||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||
| .0001 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 | ||||||||||||||||||||||||||||||
| MYL2, ALA13THR [dbSNP:rs104894363] | ||||||||||||||||||||||||||||||
| In an individual with hypertrophic cardiomyopathy (CMH10; 608758) who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified an ala13-to-thr (A13T) substitution at an evolutionarily conserved residue in the MYL2 gene product. The authors noted that preliminary investigation of other family members suggested variable expression and decreased penetrance in the cardiac disease associated with A13T. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. | ||||||||||||||||||||||||||||||
| .0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 | ||||||||||||||||||||||||||||||
| MYL2, GLU22LYS [dbSNP:rs104894368] | ||||||||||||||||||||||||||||||
| In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified a glu22-to-lys (E22K) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. Kabaeva et al. (2002) identified the E22K mutation, resulting from a heterozygous 64G-A transition in the MYL2 gene, in 7 members (4 affected and 3 with 'uncertain' phenotypes) of a family with CMH10 (608758) who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis. | ||||||||||||||||||||||||||||||
| .0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 | ||||||||||||||||||||||||||||||
| MYL2, PRO94ARG | ||||||||||||||||||||||||||||||
| In an individual with hypertrophic cardiomyopathy (CMH10; 608758), Poetter et al. (1996) identified a pro94-to-arg (P94R) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. | ||||||||||||||||||||||||||||||
| .0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 | ||||||||||||||||||||||||||||||
| MYL2, ARG58GLN [dbSNP:rs104894369] | ||||||||||||||||||||||||||||||
| In affected members of 2 families with familial hypertrophic cardiomyopathy-10 (608758), Flavigny et al. (1998) identified a 173G-A transition in exon 4 of the MYL2 gene, resulting in an arg58-to-gln (R58Q) substitution. Affected individuals were classified morphologically as Maron type 1 or 3, and the mutation segregated with the hypertrophied phenotype in both families. In a patient with asymmetric septal hypertrophic cardiomyopathy, Kabaeva et al. (2002) identified heterozygosity for the R58Q mutation. The patient had first been diagnosed at age 7 years with nonobstructive myocardial hypertrophy and underwent implantation of a cardioverter defibrillator at age 25 years after ventricular tachycardia degenerating into ventricular fibrillation was observed. She had recurrent episodes of supraventricular tachycardia, and echocardiography revealed asymmetric septal hypertrophy. DNA was not available from her sister, who had asymmetric obstructive myocardial hypertrophy and died suddenly at the age of 21 years, or from her father, who died unexpectedly at a young age and was found to have myocardial hypertrophy on autopsy. The mutation was not found in the proband's mother, who had normal cardiac findings. | ||||||||||||||||||||||||||||||
| .0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 | ||||||||||||||||||||||||||||||
| MYL2, PHE18LEU [dbSNP:rs104894370] | ||||||||||||||||||||||||||||||
| In affected members of a family segregating hypertrophic cardiomyopathy-10 (608758), Flavigny et al. (1998) identified a 52T-C transition in exon 2 of the MYL2 gene, resulting in a phe18-to-leu (F18L) substitution. Affected individuals were classified morphologically as Maron type 1, 2, or 3. | ||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||
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