Alternative titles; symbols
HGNC Approved Gene Symbol: MYL1
SNOMEDCT: 1255274002;
Cytogenetic location: 2q34 Genomic coordinates (GRCh38): 2:210,290,150-210,315,174 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q34 | Congenital myopathy 14 | 618414 | Autosomal recessive | 3 |
The MYL1 gene encodes the fast skeletal muscle-specific essential light chain (ELC) critical for myofiber development and function. There are 2 main isoforms generated by alternative splicing: MLC1F and MLC3F (summary by Ravenscroft et al., 2018).
In vertebrate fast skeletal muscle, 2 myosin alkali light chains are present: MLC1F and MLC3F. These isoforms are functionally related and may be alternately associated with myosin heavy chains in homodimer or heterodimer combinations. They are closely related in structure, having a common COOH terminal sequence of 141 amino acids. Seidel et al. (1987) isolated full-length clones for human fast fiber type myosin light chains 1 and 3 from a fetal skeletal muscle cDNA library cloned in lambda Gt11. The coding sequences were approximately 80% similar to those of chicken, mouse, and rat. For these organisms, it had been shown that both mRNAs are generated from 2 separate transcripts of 1 gene by an alternative splicing pathway which uses 2 different exons each for the N terminus and 5 common exons for the body and C terminus of the proteins. Seidel et al. (1987) presented cDNA sequences suggesting that a similar arrangement obtains in man.
Using an antibody, Ravenscroft et al. (2018) found expression of the Myl1 gene in mouse skeletal muscle, including the diaphragm, but not in heart or brain.
In vertebrate striated muscle, myosin is composed of 2 heavy chains of about 200,000 daltons each and 4 light chains of about 20,000 daltons each. The light chains are of 2 distinct types: the phosphorylatable, regulatory, or MLC2 (160781) type, and the nonphosphorylatable, alkali, or MLC1 and MLC3 types (MYL1 according to the HGM symbols). The role of myosin alkali light chains in vertebrate skeletal muscle is unclear, although in smooth muscle the alkali light chains have been shown to be involved in the active site of the myosin molecule. Several isoforms of myosin alkali light chain have been identified. These isoforms are each associated with different muscle types and are encoded by a family of myosin light chain genes (Barton and Buckingham, 1985).
Serero et al. (1987) mapped the human MYL1 gene to the region 2q32.1-qter, the same region in which the IDH1 gene (147700) is located. The Myl1 locus is closely linked to Idh1 on chromosome 1 in the mouse; thus, this is a conserved linkage. By Southern analysis of DNA from a panel of mouse-human cell hybrids, Seidel et al. (1988) also mapped MYL1 to chromosome 2. Furthermore, they demonstrated an embryonic myosin light chain that is also expressed in fetal ventricle and adult atrium; the atrial/fetal isoform is coded by a gene designated MYL4 (160770).
In 2 unrelated patients, each born of consanguineous Turkish parents, with congenital myopathy-14 (CMYP14; 618414), Ravenscroft et al. (2018) identified homozygous mutations in the MYL1 gene (160780.0001-160780.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Patient muscle was not available for cDNA analysis, but immunoblot analysis of patient muscle showed complete loss of the MYL1 protein compared to controls. Expression of one of the mutations (M163R; 160780.0002) into zebrafish with morpholino knockdown of the myl1 gene failed to rescue the abnormal muscle phenotype, indicating that this mutation resulted in a loss of function. Expression of the mutation into wildtype zebrafish resulted in a mildly abnormal muscle phenotype.
Ravenscroft et al. (2018) found that morpholino knockdown of the myl1 gene in zebrafish caused curved bodies, bent tails, and a marked reduction in touch-evoked escape responses compared to controls. Analysis of muscle structure showed reduced birefringence, indicating abnormal structure, and abnormally wavy, sparse, and disordered myofibers. The findings indicated that myl1 is required for the normal formation and maintenance of myofibers.
In a male infant, born of consanguineous Turkish parents (family 1), with congenital myopathy-14 (CMYP14; 618414), Ravenscroft et al. (2018) identified a homozygous A-to-G transition in intron 4 of the MYL1 gene (c.479-2A-G) that was predicted to result in a splice site alteration and the in-frame skipping of exon 5, which would remove 13% of the protein sequence, including the end of the highly conserved second EF-hand motif. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, ExAC, or gnomAD databases. Each unaffected parent was a carrier of the mutation. Patient muscle was not available for cDNA analysis, but immunoblot analysis of patient muscle showed complete loss of the MYL1 protein compared to controls.
In a 3-year-old girl, born of consanguineous Turkish parents (family 2), with congenital myopathy-14 (CMYP14; 618414), Ravenscroft et al. (2018) identified a homozygous c.488T-G transversion in exon 5 of the MYL1 gene, resulting in a met163-to-arg (M163R) substitution at a highly conserved residue in the second EF-hand domain. The mutation, which was found by exome sequencing and analysis of candidate muscle disease genes, was confirmed by Sanger sequencing. It was not found in the 1000 Genomes Project, ExAC, or gnomAD databases. Each unaffected parent was a carrier of the mutation. Patient muscle was not available for cDNA analysis, but immunoblot analysis of patient muscle showed complete loss of the MYL1 protein compared to controls. Molecular modeling suggested that the mutation could alter the binding of MYL1 to the myosin heavy chain. Expression of the mutation into zebrafish with morpholino knockdown of the myl1 gene failed to rescue the abnormal muscle phenotype, indicating that the mutation results in a loss of function. Expression of the mutation into wildtype zebrafish resulted in a mildly abnormal muscle phenotype.
Barton, P. J. R., Buckingham, M. E. The myosin alkali light chain proteins and their genes. Biochem. J. 231: 249-261, 1985. [PubMed: 3904738] [Full Text: https://doi.org/10.1042/bj2310249]
Cohen-Haguenauer, O., Barton, P. J. R., Van Cong, N., Serero, S., Gross, M.-S., Jegou-Foubert, C., de Tand, M.-F., Robert, B., Buckingham, M., Frezal, J. Assignment of the human fast skeletal muscle myosin alkali light chains gene (MLC1F/MLC3F) to 2q32.1-2qter. Hum. Genet. 78: 65-70, 1988. [PubMed: 3422212] [Full Text: https://doi.org/10.1007/BF00291237]
Ravenscroft, G., Zaharieva, I. T., Bortolotti, C. A., Lambrughi, M., Pignataro, M., Borsari, M., Sewry, C. A., Phadke, R., Haliloglu, G., Ong, R., Goullee, H., Whyte, T., UK10K Consortium, Manzur, A., Talim, B., Kaya, U., Osborn, D. P. S., Forrest, A. R. R., Laing, N. G., Muntoni, F. Bi-allelic mutations in MYL1 cause a severe congenital myopathy. Hum. Molec. Genet. 27: 4263-4272, 2018. [PubMed: 30215711] [Full Text: https://doi.org/10.1093/hmg/ddy320]
Seidel, U., Bober, E., Winter, B., Lenz, S., Lohse, P., Arnold, H. H. The complete nucleotide sequences of cDNA clones coding for human myosin light chains 1 and 3. Nucleic Acids Res. 15: 4989 only, 1987. [PubMed: 3601661] [Full Text: https://doi.org/10.1093/nar/15.12.4989]
Seidel, U., Bober, E., Winter, B., Lenz, S., Lohse, P., Goedde, H. W., Grzeschik, K. H., Arnold, H. H. Alkali myosin light chains in man are encoded by a multigene family that includes the adult skeletal muscle, the embryonic or atrial, and nonsarcomeric isoforms. Gene 66: 135-146, 1988. [PubMed: 2458299] [Full Text: https://doi.org/10.1016/0378-1119(88)90231-4]
Serero, S., Barton, P., Van Cong, N., Cohen-Haguenauer, O., Robert, B., Buckingham, M., Frezal, J. Assignment of the human fast skeletal muscle myosin alkali light chains gene (MLC1F/MLC3F) to 2q32.1-2qter. (Abstract) Cytogenet. Cell Genet. 46: 690 only, 1987.