Alternative titles; symbols
HGNC Approved Gene Symbol: MYL3
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:46,857,872-46,882,182 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Cardiomyopathy, hypertrophic, 8 | 608751 | Autosomal dominant; Autosomal recessive | 3 |
In all eukaryotes, myosin plays a major role in the maintenance of cell shape and in cellular movement; in association with actin and other contractile proteins, it is also a major structural component of the muscle sarcomere. Myosin is composed of 2 heavy chains associated with 4 light chains belonging to 2 distinct classes: 2 phosphorylatable, or regulatory, light chains (e.g., MYL2, 160781), and 2 nonphosphorylatable, or alkali, light chains, such as MYL3 (summary by Cohen-Haguenauer et al., 1989).
Hoffmann et al. (1988) cloned human ventricular myosin light chain-1, encoding a deduced protein of 195 amino acids.
Fodor et al. (1989) found that the MYL3 gene has 7 exons, the last of which is completely untranslated 3-prime sequence.
Darras et al. (1987) and Fodor et al. (1989) used a fragment from the 3-prime end of the human myosin alkali light chain gene, isolated by screening a partial genomic library with rat skeletal myosin light chain cDNA, in studies of somatic cell hybrids. The gene was found to map to 3p. In the mouse, the Myl3 gene on distal chromosome 9 codes the ventricular and slow skeletal muscle isoforms. Other loci in that area, such as Bgl and Acy, are homologous to genes on human chromosome 3p. It is possible that the gene mapped by Darras et al. (1987) is the human homolog of mouse Myl3; thus the designation MYL3 is used for the human locus.
Using a panel of man-rodent somatic cell hybrids, Cohen-Haguenauer et al. (1989) mapped the MYL3 gene to chromosome 3. This finding was in keeping with the assignment of the corresponding gene to mouse chromosome 9.
Laugwitz et al. (2001) showed that caspase-3 (600636) activation directly influences contractile performance of failing ventricular myocytes, and can be corrected via adenovirus-mediated gene delivery of the potent caspase inhibitor p35 with a positive impact on contractility. To determine the molecular mechanism by which activated caspase-3 causes a deterioration of cardiac function, Moretti et al. (2002) used a modified yeast 2-hybrid system to screen for caspase-3 interacting proteins of the cardiac cytoskeleton. They identified ventricular essential myosin light chain (MYL3), symbolized vMLC1 by the authors, as a target of caspase-3. They demonstrated that MYL3 cleavage in failing myocardium in vivo was associated with a morphologic disruption of the organized MYL3 staining of sarcomeres, and with a reduction in myocyte contractile performance. Adenoviral gene transfer of p35 in vivo prevented caspase-3 activation and MYL3 cleavage, with positive impact on contractility. These data suggested that direct cleavage of the myosin light chain by activated caspase-3 may contribute to depression of myocyte function by altering crossbridge interaction between myosin and actin molecules. Therefore, activation of apoptotic pathways in the heart may lead to contractile dysfunction before cell death.
Poetter et al. (1996) analyzed the MYL3 gene in 383 unrelated probands with hypertrophic cardiomyopathy (see CMH8, 608751) and identified a heterozygous missense mutation at a conserved residue (M149V; 160790.0001) that segregated with disease in a large 3-generation family. Linkage analysis of the mutation against hypertrophy gave a lod score of 6.2 with no recombinants. Six of 13 affected family members had unusual mid-left ventricular chamber thickening on echocardiography. Poetter et al. (1996) screened the MYL3 gene in 16 additional CMH patients with similar mid-left ventricular chamber thickening and identified a different heterozygous missense mutation (R154H; 160790.0002) in a young boy with massive chamber obstruction. Neither these nor any other mutations in MYL3 were found in 378 control chromosomes or 762 chromosomes from unrelated CMH kindreds. Poetter et al. (1996) also analyzed the MYL2 gene (160781) in CMH patients and identified 3 different heterozygous mutations in 5 affected individuals, 4 of whom had 'strikingly similar' mid-left ventricular chamber hypertrophy (see CMH10, 608758).
In 3 sibs of a consanguineous family with early-onset hypertrophic cardiomyopathy characterized by midcavitary hypertrophy and restrictive physiology, Olson et al. (2002) performed haplotype analysis using polymorphic DNA markers spanning genes known to cause hypertrophic cardiomyopathy. The results suggested that, in keeping with the consanguineous family history, the phenotype might be an autosomal recessive form of CMH caused by mutation in MYL3. A homozygous MYL3 mutation, glu143 to lys (E143K; 160790.0003), was subsequently identified in the proband. The authors suggested that, in contrast to autosomal dominant CMH mutations in which functional studies demonstrate a dominant-negative effect, E143K was likely to cause loss of function. In support of this hypothesis, the authors found that heterozygotes were unaffected on the basis of electrocardiography and echocardiography. In addition, this mutation affected an amino acid in a surface-exposed loop of the essential light chain and was unlikely to disrupt protein conformation or stability. Site-directed mutagenesis of the corresponding loop domain (Ho and Chisholm, 1997) had no effect on binding between myosin heavy and light chains, but significantly reduced actin-activated ATPase activity and in vitro motility. Thus, Olson et al. (2002) concluded that this family demonstrated a true autosomal recessive form of CMH8, characterized by a unique pattern of hypertrophy previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al. (1982), in which 6 of 12 affected members had typical asymmetric hypertrophy and 6 had ventricular septal hypertrophy that was localized to the apical region of the left ventricle, Arad et al. (2005) identified heterozygosity for the M149V mutation. Arad et al. (2005) noted that because the classification of hypertrophy as midcavitary or apical might in part reflect the evolution of diagnostic imaging techniques from angiography, by which midcavitary hypertrophy was historically recognized, to echocardiography and MRI, these may represent overlapping morphologies.
In affected members of a large 3-generation family segregating autosomal dominant hypertrophic cardiomyopathy (CMH8; 608751), Poetter et al. (1996) identified heterozygosity for an A-G transition in the MYL3 gene, resulting in a met149-to-val (M149V) substitution at a highly conserved residue. Six of 13 affected family members had unusual mid-left ventricular chamber thickening on echocardiography. An in vitro motility assay of ventricular myosins from 3 mutation-positive individuals demonstrated an increased rate of actin translocation compared to controls. Soleus or deltoid muscle biopsies from the same 3 patients showed myopathic changes and a ragged-red fiber pattern characteristic of primary mitochondrial disease; cytochrome oxidase-positive subsarcolemmal accumulations were confirmed to be mitochondria by electron microscopy. The M149V mutation was not found in 378 control chromosomes or in 762 chromosomes from unrelated CMH kindreds.
In the proband from a CMH family previously described by Maron et al. (1982), in which 6 of 12 affected members had typical asymmetric hypertrophy and 6 had ventricular septal hypertrophy that was localized to the apical region of the left ventricle, Arad et al. (2005) identified heterozygosity for the M149V mutation. Two members of the family had died of heart failure, at 35 and 54 years of age, respectively, and sudden death had occurred in 3 individuals, at ages 26, 33, and 35 years, respectively.
In a young boy with hypertrophic cardiomyopathy (CMH8; 608751) and massive mid-left ventricular chamber obstruction, Poetter et al. (1996) identified an arg154-to-his (R154H) substitution at a highly conserved residue in the MYL3 gene. The mutation was not found in 378 control chromosomes or in 762 chromosomes from unrelated CMH kindreds.
Olson et al. (2002) reported a consanguineous family in which 3 sibs had presented with childhood-onset CMH characterized by midcavitary left-ventricular hypertrophy (CMH8; 608751). Both parents had completely normal hearts in their 40s. Mutation screening in a surviving affected sib revealed a homozygous missense G-to-A point mutation at codon 143 of the MYL3 gene, resulting in a glutamic acid-to-lysine (E143K) substitution. Heterozygotes had normal hearts. Sequence alignment of myosin essential light chains demonstrated high conservation of glutamic acid at position 143 across species. The E143K mutation was absent from 150 normal control DNA samples. The authors concluded that this was a true autosomal recessive form of CMH8.
In a 22-year-old woman from El Salvador with cardiomyopathy, Caleshu et al. (2011) sequenced the exons and exon-intron boundaries of 8 known cardiomyopathy-associated genes and identified homozygosity for the E143K mutation in the MYL3 gene. The patient was also found to be heterozygous for a G57E polymorphism in the MYL2 gene (160781); her asymptomatic 45-year-old mother, who had a normal transthoracic echocardiogram, electrocardiogram, and physical examination, was heterozygous for both the E143K mutation in MYL3 and the G57E polymorphism in MYL2. The patient, who had a prior diagnosis of childhood asthma, presented with worsening dyspnea and fatigue over the previous year, and transthoracic echocardiogram revealed severe biatrial enlargement with preserved biventricular systolic function and no left ventricular hypertrophy or valvular disease; Doppler evaluation suggested advanced left ventricular diastolic dysfunction. Left and right heart catheterization showed elevated filling pressures bilaterally, with a prominent y-descent, a suggestion of a 'dip-and-plateau,' and ventricular concordance, all features described in restrictive cardiomyopathy (RCM). Right ventricular endomyocardial biopsy revealed marked myocyte hypertrophy and myofiber disarray with interstitial fibrosis. The patient went on to develop recurrent syncope and had an automatic implantable cardiac defibrillator placed; she underwent orthotopic heart transplantation 6 months after diagnosis with cardiomyopathy.
Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112: 2805-2811, 2005. [PubMed: 16267253] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.547448]
Caleshu, C., Sakhuja, R., Nussbaum, R. L., Schiller, N. B., Ursell, P. C., Eng, C., De Marco, T., McGlothlin, D., Burchard, E. G., Rame, J. E. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. Am. J. Med. Genet. 155A: 2229-2235, 2011. [PubMed: 21823217] [Full Text: https://doi.org/10.1002/ajmg.a.34097]
Cohen-Haguenauer, O., Barton, P. J. R., Van Cong, N., Cohen, A., Masset, M., Buckingham, M., Frezal, J. Chromosomal assignment of two myosin alkali light-chain genes encoding the ventricular/slow skeletal muscle isoform and the atrial/fetal muscle isoform (MYL3, MYL4). Hum. Genet. 81: 278-282, 1989. [PubMed: 2784124] [Full Text: https://doi.org/10.1007/BF00279004]
Darras, B. T., Fodor, B., Vanin, E., Francke, U. A human myosin alkali light chain gene mapped to chromosome 3. (Abstract) Cytogenet. Cell Genet. 46: 603, 1987.
Fodor, W. L., Darras, B., Seharaseyon, J., Falkenthal, S., Francke, U., Vanin, E. F. Human ventricular/slow twitch myosin alkali light chain gene characterization, sequence, and chromosomal location. J. Biol. Chem. 264: 2143-2149, 1989. [PubMed: 2789520]
Ho, G., Chisholm, R. L. Substitution mutations in the myosin essential light chain lead to reduced actin-activated ATPase activity despite stoichiometric binding to the heavy chain. J. Biol. Chem. 272: 4522-4527, 1997. [PubMed: 9020178] [Full Text: https://doi.org/10.1074/jbc.272.7.4522]
Hoffmann, E., Shi, Q. W., Floroff, M., Mickle, D. A. G., Wu, T.-W., Olley, P. M., Jackowski, G. Molecular cloning and complete nucleotide sequence of a human ventricular myosin light chain 1. Nucleic Acids Res. 16: 2353, 1988. [PubMed: 3357795] [Full Text: https://doi.org/10.1093/nar/16.5.2353]
Laugwitz, K.-L., Moretti, A., Weig, H.-J., Gillitzer, A., Pinkernell, K., Ott, T., Pragst, I., Stadele, C., Seyfarth, M., Schomig, A., Ungerer, M. Blocking caspase-activated apoptosis improves contractility in failing myocardium. Hum. Gene Ther. 12: 2051-2063, 2001. [PubMed: 11747596] [Full Text: https://doi.org/10.1089/10430340152677403]
Maron, B. J., Bonow, R. O., Seshagiri, T. N. R., Roberts, W. C., Epstein, S. E. Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982. [PubMed: 6211078] [Full Text: https://doi.org/10.1016/0002-9149(82)90200-4]
Moretti, A., Weig, H.-J., Ott, T., Seyfarth, M., Holthoff, H.-P., Grewe, D., Gillitzer, A., Bott-Flugel, L., Schomig, A., Ungerer, M., Laugwitz, K.-L. Essential myosin light chain as a target for caspase-3 in failing myocardium. Proc. Nat. Acad. Sci. 99: 11860-11865, 2002. [PubMed: 12186978] [Full Text: https://doi.org/10.1073/pnas.182373099]
Olson, T. M., Karst, M. L., Whitby, F. G., Driscoll, D. J. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 105: 2337-2340, 2002. [PubMed: 12021217] [Full Text: https://doi.org/10.1161/01.cir.0000018444.47798.94]
Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nature Genet. 13: 63-69, 1996. [PubMed: 8673105] [Full Text: https://doi.org/10.1038/ng0596-63]