Alternative titles; symbols
HGNC Approved Gene Symbol: MYL4
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:47,189,433-47,227,650 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.32 | ?Atrial fibrillation, familial, 18 | 617280 | Autosomal dominant | 3 |
Strohman et al. (1983) showed that human fetal muscle contains a fetal-specific myosin light chain, which is absent from adult muscle.
By Southern blot analysis of DNA from somatic cell hybrids, Cohen-Haguenauer et al. (1989) assigned the MYL4 gene (which codes the atrial/fetal muscle isoform of myosin alkali light chains) to chromosome 17. The corresponding gene in the mouse has been assigned to chromosome 11.
By Southern analysis of somatic cell hybrids, Seharaseyon et al. (1990) mapped the embryonic/atrial myosin alkali light chain gene to 17q and the corresponding mouse gene to chromosome 11.
In 5 affected members of a family with atrial fibrillation (ATFB18; 617280), Orr et al. (2016) identified heterozygosity for a missense mutation in the MYL4 gene (E11K; 160770.0001). The mutation segregated with disease in the family and was not found in controls or in public variant databases.
Orr et al. (2016) generated a transgenic zebrafish line expressing the mutation corresponding to E11K in human MYL4, E17K in the zebrafish ortholog cmlc1, under control of the atrial-specific Myh6 promoter. Electrocardiography of adult transgenic fish showed abnormalities paralleling those observed in human patients, including irregular sinoatrial impulse generation, bradycardia, and prolonged P-wave duration, reflecting slowed atrial conduction. Transgenic zebrafish showed a 25% decrease in heart rate compared with controls, and 8 (73%) of 11 transgenics exhibited severe bradycardia. Dissected adult hearts demonstrated a 1.6-fold increase in atrial surface area of transgenic zebrafish compared to controls, whereas no statistical difference in ventricular surface area was observed. In addition, transgenic atrial size exceeded ventricular size, with an atrial:ventricular area ratio of 1.41, compared to 0.65 for controls. Imaging of myofibrils from transgenic atria at 5 days postfertilization (dpf) showed disorganization, and some individual sarcomeres appeared stippled and blurred, indicating abnormal organization of H-zones and Z-discs. Electron microscopy on adult zebrafish hearts showed that Z-discs in transgenic atria were largely absent. Analysis of zebrafish myocardial function at 3, 5, and 10 dpf showed no statistically significant functional differences between groups, suggesting that myofibrillar disarray precedes atrial dysfunction and arrhythmia.
In 5 affected members of a family with atrial fibrillation, conduction disease, and reduced left atrial function (ATFB18; 617280), Orr et al. (2016) identified heterozygosity for a G-A transition at chr17:45,286,819 (chr17.45,286,819G-A, GRCh37) in the MYL4 gene, resulting in a glu11-to-lys (E11K) substitution at a highly conserved residue within the filamentous actin-binding N terminus. The mutation segregated with disease in the family and was not found in 10 unrelated controls or in the dbSNP, 1000 Genomes Project, or NHLBI Exome Variant Server databases.
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]
Orr, N., Arnaout, R., Gula, L. J., Spears, D. A., Leong-Sit, P., Li, Q., Tarhuni, W., Reischauer, S., Chauhan, V. S., Borkovich, M., Uppal, S., Adler, A., Coughlin, S. R., Stainier, D. Y. R., Gollob, M. H. A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nature Commun 7: 11303, 2016. Note: Electronic Article. [PubMed: 27066836] [Full Text: https://doi.org/10.1038/ncomms11303]
Seharaseyon, J., Bober, E., Hsieh, C.-L., Fodor, W. L., Francke, U., Arnold, H.-H., Vanin, E. F. Human embryonic/atrial myosin alkali light chain gene: characterization, sequence and chromosomal location. Genomics 7: 289-293, 1990. [PubMed: 2129532] [Full Text: https://doi.org/10.1016/0888-7543(90)90554-8]
Strohman, R. C., Micou-Eastwood, J., Glass, C. A., Matsuda, R. Human fetal muscle and cultured myotubes derived from it contain a fetal-specific myosin light chain. Science 221: 955-957, 1983. [PubMed: 6879193] [Full Text: https://doi.org/10.1126/science.6879193]