Alternative titles; symbols
HGNC Approved Gene Symbol: MYL2
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38): 12:110,910,845-110,921,449 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | Cardiomyopathy, hypertrophic, 10 | 608758 | Autosomal dominant | 3 |
| Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy | 619424 | Autosomal recessive | 3 |
The 2 pairs of light chains of muscle myosins are called essential light chains (ELC) and regulatory light chains (RLC). 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, skeletal muscle, and cardiac muscle. An increase in ventricular MYL2 is observed in the hypertrophied myocardium of cardiac patients with valvular stenosis (summary by Poetter et al., 1996; Macera et al., 1992; Weterman et al., 2013).
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.
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 (CMH10; 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.
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.
Hypertrophic Cardiomyopathy 10
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.
Infantile-Onset Myofibrillar Myopathy 12 with Cardiomyopathy
In 11 infants from 5 unrelated Dutch families and 2 sibs from an Italian family with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified homozygous or compound heterozygous mutation in the MYL2 gene (160781.0006-160781.0008) that segregated with the disorder in the families. The mutations, 1 splice site and 2 frameshifts, all occurred in the last exon of the gene and were predicted to result in the production of C-terminally truncated proteins. The mutations, which were found by a combination of homozygosity mapping and candidate gene sequencing or whole-exome sequencing, were confirmed by Sanger sequencing. All patients died of cardiac failure by 6 months of age. The carrier parents were unaffected. Analysis of patient tissue from the Dutch patients showed absence of the full-length MYL2 protein and decreased expression of mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by Barth et al. (1998). Haplotype analysis indicated a founder effect for the Dutch mutation (160781.0006).
In a male infant, born of consanguineous parents, with MFM12, Manivannan et al. (2020) identified a homozygous frameshift mutation in the last exon of the MYL2 gene (160781.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected; 3 additional sibs of the proband died of a similar disorder in infancy. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect.
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.
In an individual with hypertrophic cardiomyopathy (CMH10; 608758) who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified heterozygosity for 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.
In a 73-year-old man with mild left ventricular hypertrophy attributed to severe aortic stenosis, who had postoperative resolution of symptoms after valve replacement and single-vessel coronary artery bypass surgery, Li et al. (2017) identified heterozygosity for the A13T variant in the MYL2 gene. The authors noted that an unequivocal diagnosis of CMH could not be established in this patient. His son and daughter, who were heterozygous for the A13T variant in addition to pathogenic variants in the TTN (188840) and ALPK3 (617608) genes, exhibited a severe CMH phenotype with left ventricular outflow obstruction (see 618052).
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 heterozygosity for 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 who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis.
In an individual with hypertrophic cardiomyopathy (CMH10; 608758), Poetter et al. (1996) identified heterozygosity for 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.
In affected members of 2 families with familial hypertrophic cardiomyopathy-10 (CMH10; 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.
In affected members of a family segregating hypertrophic cardiomyopathy-10 (CMH10; 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.
In 11 patients from 8 unrelated Dutch families with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified a homozygous G-to-C transversion (c.403-1G-C) in the last acceptor splice site of the MYL2 gene. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The parents were unaffected carriers of the mutations. RT-PCR analysis of patient tissue confirmed that the mutation escaped nonsense-mediated mRNA decay and resulted in a frameshift and premature termination in the C terminus. Immunohistochemical staining and Western blot analysis of patient skeletal muscle tissue showed absence of the full-length MYL2 protein and decreased expression of the mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by Barth et al. (1998). Haplotype analysis was consistent with a founder effect.
In 2 Italian brothers with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified compound heterozygous frameshift mutations affecting adjacent nucleotides in the last exon of the MYL2 gene: c.431delC, causing Pro144LeufsTer2, and c.432delT (160781.0008), causing Asp145ThrfsTer2. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but they were predicted to result in the production of C-terminally truncated proteins.
For discussion of the 1-bp deletion (c.432delT) in the MYL2 gene, resulting in a frameshift and premature termination (Asp145ThrfsTer2), that was found in compound heterozygous state in 2 sibs with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424) by Weterman et al. (2013), see 160781.0007.
In a male infant, born of consanguineous parents, with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Manivannan et al. (2020) identified a homozygous 2-bp deletion (c.431_432delCT, NM_000432.3) in exon 6 of the MYL2 gene, predicted to result in a frameshift and termination (Pro144ArgfsTer57) with extension of the reading frame into the 3-prime UTR, leading to the addition of 36 amino acids to the C terminus. The mutation was predicted to disrupt the EF-hand domains in the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. Family history revealed 3 additional sibs of the proband with a similar disorder resulting in death in infancy due to cardiac failure.
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Macera, M. J., Szabo, P., Wadgaonkar, R., Siddiqui, M. A. Q., Verma, R. S. Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3. Genomics 13: 829-831, 1992. [PubMed: 1386340] [Full Text: https://doi.org/10.1016/0888-7543(92)90161-k]
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Szczesna-Cordary, D., Guzman, G., Zhao, J., Hernandez, O., Wei, J., Diaz-Perez, Z. The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice. J. Cell Sci. 118: 3675-3683, 2005. [PubMed: 16076902] [Full Text: https://doi.org/10.1242/jcs.02492]
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Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain 136: 282-293, 2013. [PubMed: 23365102] [Full Text: https://doi.org/10.1093/brain/aws293]