HGNC Approved Gene Symbol: MYO3A
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38) : 10:25,934,229-26,212,532 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.1 | Deafness, autosomal dominant 90 | 620722 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 30 | 607101 | Autosomal recessive | 3 |
Actin-dependent motor proteins are members of the large myosin superfamily and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as MYO3A, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors (summary by Dose and Burnside, 2000).
By RT-PCR with degenerate primers of a retina and retinal pigment epithelium (RPE) cell line cDNA library, Dose and Burnside (2000) isolated a cDNA encoding MYO3A. The deduced 1,616-amino acid protein contains an N-terminal kinase domain with homology to the serine/threonine kinase HGK (MAP4K4; 604666), followed by a motor region and 3 approximately 23-residue IQ motifs, which are involved in calmodulin/light chain binding. Two of the IQ motifs are in conserved locations in the neck region, while the third is uniquely located in the center of the tail domain. Northern blot analysis revealed a 6.5-kb transcript that was weakly expressed in pancreas and strongly expressed in retina. It was not expressed in a native RPE/choroid mixture, but it was readily detectable in an RPE cell line. A probe to the kinase domain also detected transcripts of 4.0 and 2.5 kb. Dose and Burnside (2000) proposed that the calmodulin-binding sites of MYO3A may be important in vision in accordance with their role in the ninaC protein in Drosophila photoreceptors.
Walsh et al. (2011) stated that mouse Myo3a is expressed in vestibular hair cells and in the inner ear, where it localizes to stereocilia tips in a thimble-like pattern.
By somatic cell hybrid and radiation hybrid analyses, Dose and Burnside (2000) mapped the MYO3A gene to chromosome 10p11.1.
Mecklenburg et al. (2015) found that Drosophila and human MORN4 (617736) bound to MYO3A, but not MYO3B (610040). In transfected COS-7 cells, human MORN4 and MYO3A colocalized to actin-rich filopodia extensions. Deletion analysis showed that the tail domain of MYO3A was required for binding to MORN4. In the absence of MYO3A, MORN4 showed diffuse cytoplasmic and nuclear localization, but in the presence of MYO3A, MORN4 localized to filopodia tips. MORN4 also enhanced tip localization of MYO3A. Mecklenburg et al. (2015) hypothesized that MORN4 functions as an adaptor protein that may enhance the association of MYO3A with membranes or facilitate its association with scaffolding and actin-based structures.
Autosomal Recessive Deafness 30
Walsh et al. (2002) showed that normal hearing in humans requires myosin IIIA, which is the human homolog of ninaC, a class III myosin that is required for normal vision in Drosophila. In an extended Israeli family, they showed that nonsyndromic progressive hearing loss (DFNB30; 607101) is caused by 3 different recessive, loss-of-function mutations in myosin IIIA (606808.0001-606808.0003). Of 18 affected relatives in this family, 7 were homozygous and 11 were compound heterozygous for pairs of mutant alleles. Expression of mammalian myosin IIIA is highly restricted, with the strongest expression in retina and cochlea. The involvement of homologous class III myosins in both Drosophila vision and human hearing is an evolutionary link between these sensory systems.
In a Lebanese woman with cutis laxa type IA (ARCL1A; 620780), who also had mild bilateral hearing impairment, Bizzari et al. (2020) identified homozygosity for a 2-bp deletion (c.1370_1371delGA; rs760866131) in the MYO3A gene, causing a frameshift predicted to result in a premature termination codon (Arg457AsnfsTer25). The mutation was not present in her brother, who also had ARCL1A but had normal hearing. The mutation was not found in the Saudi Human Genome Program database, but was present in the gnomAD database at a minor allele frequency of 0.001%, only in heterozygous state.
Autosomal Dominant Deafness 90
In 36 patients from 2 families with DFNA90 (620722), Dantas et al. (2018) identified heterozygosity for a missense mutation in the MYO3A gene (L697W; 606808.0004). Two individuals, aged 28 and 29 years, from family 1 and 1 individual, aged 30 years, from family 2 were heterozygous for the L697W mutation but did not have hearing loss. Dantas et al. (2018) noted that these patients were at or below the average age of hearing loss onset in the families and hypothesized that these were cases of nonpenetrance or late-onset. Expression of the L697W mutation in COS cells resulted in a lower maximal ATPase rate and a decrease in actin sliding activity compared to wildtype MYO3A. The mutant MYO3A also resulted in decreased actin protrusion initiation and elongation of stereocilia. When mutant and wildtype MYO3A were coexpressed, the mutant MYO3A displaced wildtype MYO3A at stereocilia tips, resulting in a dominant-negative effect.
Gunther et al. (2022) characterized the L697W mutation in the MYO3A gene (606808.0004) in COS-7 cells. The mutant MYO3A protein displayed delayed ATP hydrolysis and subsequent delayed release of ADP, thus slowing detachment. Further studies demonstrated that mutant MYO3A localized properly to the filopodia tip but resulted in reduced velocity of filopodia extension, average filopodia length, and speed of actin gliding. Gunther et al. (2022) concluded that motor activity of MYO3A is important for regulation of actin length protrusion.
Doll et al. (2020) identified a heterozygous mutation in the MYO3A gene (L239P; 606808.0005) in 7 affected members of a 3-generation family with DFNA90.
Associations Pending Confirmation
By whole-exome sequencing in a family segregating nonsyndromic hearing loss, Grati et al. (2016) identified a possibly pathogenic heterozygous missense variant (G488E; c.1463G-A, rs145970949) in the MYO3A gene. The G488E variant was present in the affected father and his 3 affected children; however, the mother also had hearing loss and no causative gene mutations were reported for her. Expression of MYO3A with the G488D mutation resulted in inability of the mutant protein to accumulate in or elongate filopodia tips.
Walsh et al. (2011) created a line of mice carrying the homozygous nonsense mutation Y1041X, corresponding to human Y1042X. Homozygous mutant mice displayed significant and progressive hearing loss, but no vestibular abnormalities. Hearing loss was accompanied by degenerative changes in both inner and outer hair cells, with greater hair cell loss toward the base, reflecting more severe hearing loss at higher frequencies.
Walsh et al. (2002) studied a family that traced its ancestry to the Jewish community of Mosul, Iraq. This community dated to 586 B.C. and was highly endogamous, with considerable emigration but little immigration, for more than 2,500 years. Most remaining Jewish residents of Mosul, including this family, migrated to Israel in 1950-1951. Three generations of the family had experienced bilateral progressive hearing loss, which first affected the high frequencies (DFNB30; 607101). Hearing loss began in the second decade, and by age 50, was severe in high and middle frequencies and moderate at low frequencies. Vision and balance of all affected individuals were normal. Inheritance of deafness in this family was likely recessive with age-dependent penetrance, although dominant inheritance could not be excluded. Sequencing of the MYO3A gene from genomic DNA revealed 3 different mutations of this gene cosegregating with hearing loss. A nonsense mutation at codon 1043, 3126T-G, caused protein truncation at the junction of the head and neck domains of the gene and was associated with 3 different extended haplotypes in the family. A mutation in the splice acceptor of intron 17, 1777(-12)G-A (606808.0002), led to deletion of exon 18 and protein truncation at codon 668 in the myosin head domain. A mutation in the splice acceptor of intron 8, 732(-2)A-G (606808.0003), led to an unstable message, as revealed by the absence of message from this allele in persons who carried the mutation in their genomic DNA. These 3 mutations fully explained the hearing loss in this family, in that there was complete concordance of MYO3A genotypes and hearing loss. All homozygotes and compound heterozygotes were deaf; all simple heterozygotes were carriers with normal hearing. Variability in age of onset of hearing loss could be explained. Between age 25 and 50 years, hearing across all frequencies was significantly poorer among individuals homozygous for the nonsense mutation than among individuals heterozygous for the nonsense mutation in combination with either of the splice mutations. Hearing loss was equally severe in all affected individuals by the sixth decade. Walsh et al. (2011) found that all ocular motor and vestibular measures were normal in family N, subject IV:2.
See 606808.0001 and Walsh et al. (2002).
See 606808.0001 and Walsh et al. (2002).
In 36 patients from 2 Brazilian families with autosomal dominant hearing loss-90 (DFNA90; 620722), Dantas et al. (2018) identified heterozygosity for a c.2090T-G transversion (c.2090T-G, NM_017433.4) in the MYO3A gene, resulting in a leu697-to-trp (L697W) substitution. The mutation was identified by linkage analysis, whole-exome sequencing, and Sanger sequencing. The variant was not present in the 1000 Genomes Project, ESP, and ExAC databases. Expression of the L697W mutation in COS cells resulted in a lower maximal ATPase rate and a decrease in actin sliding activity compared to wildtype MYO3A. The mutant MYO3A also resulted in decreased actin protrusion initiation and elongation of stereocilia. When mutant and wildtype MYO3A were coexpressed, the mutant MYO3A displaced wildtype MYO3A at stereocilia tips, resulting in a dominant-negative effect.
Gunther et al. (2022) characterized the L697W mutation in the MYO3A gene in COS-7 cells. The mutant MYO3A protein displayed delayed ATP hydrolysis and subsequent delayed release of ADP, thus slowing detachment. Further studies demonstrated that the mutant MYO3A localized properly to the filopodia tip but resulted in reduced velocity of filopodia extension, average filopodia length, and speed of actin gliding.
In 7 patients from a 3-generation family with autosomal dominant deafness-90 (DFNA90; 620722), Doll et al. (2020) identified heterozygosity for a c.716T-C transition (c.716T-C, NM_017433.4) in exon 8 of the MYO3A gene, resulting in a leu239-to-pro (L239P) substitution. The mutation was identified by whole-exome sequencing in the index patient and segregated with disease in the family. Functional studies in patient cells were not performed.
Bizzari, S., El-Bazzal, L., Nair, P., Younan, A., Stora, S., Mehawej, C., El-Hayek, S., Delague, V., Megarbane, A. Recessive marfanoid syndrome with herniation associated with a homozygous mutation in fibulin-3. Europ. J. Med. Genet. 63: 103869, 2020. [PubMed: 32006683] [Full Text: https://doi.org/10.1016/j.ejmg.2020.103869]
Dantas, V. G. L., Raval, M. H., Ballesteros, A., Cui, R., Gunther, L. K., Yamamoto, G. L., Alves, L. U., Bueno, A. S., Lezirovitz, K., Pirana, S., Mendes, B. C. A., Yengo, C. M., Kachar, B., Mingroni-Netto, R. C. Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss. Sci. Rep. 8: 8706, 2018. [PubMed: 29880844] [Full Text: https://doi.org/10.1038/s41598-018-26818-2]
Doll, J., Hofrichter, M. A. H., Bahena, P., Heihoff, A., Segebarth, D., Muller, T., Dittrich, M., Haaf, T., Vona, B. A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family. Molec. Genet. Genomic Med. 8: e1343, 2020. [PubMed: 32519820] [Full Text: https://doi.org/10.1002/mgg3.1343]
Dose, A. C., Burnside, B. Cloning and chromosomal localization of a human class III myosin. Genomics 67: 333-342, 2000. [PubMed: 10936054] [Full Text: https://doi.org/10.1006/geno.2000.6256]
Grati, M., Yan, D., Raval, M. H., Walsh, T., Ma, Q., Chakchouk, I., Kannan-Sundhari, A., Mittal, R., Masmoudi, S., Blanton, S. H., Tekin, M., King, M. C., Yengo, C. M., Liu, X. Z. MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Hum. Mutat. 37: 481-487, 2016. [PubMed: 26841241] [Full Text: https://doi.org/10.1002/humu.22961]
Gunther, L. K., Cirilo, J. A., Desetty, R., Yengo, C. M. Deafness mutation in the MYO3A motor domain impairs actin protrusion elongation mechanism. Molec. Biol. Cell 33: ar5, 2022. [PubMed: 34788109] [Full Text: https://doi.org/10.1091/mbc.E21-05-0232]
Mecklenburg, K. L., Freed, S. A., Raval, M., Quintero, O. A., Yengo, C. M., O'Tousa, J. E. Invertebrate and vertebrate class III myosins interact with MORN repeat-containing adaptor proteins. PLoS One 10: e0122502, 2015. Note: Electronic Article. [PubMed: 25822849] [Full Text: https://doi.org/10.1371/journal.pone.0122502]
Walsh, T., Walsh, V., Vreugde, S., Hertzano, R., Shahin, H., Haika, S., Lee, M. K., Kanaan, M., King, M.-C., Avraham, K. B. From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc. Nat. Acad. Sci. 99: 7518-7523, 2002. [PubMed: 12032315] [Full Text: https://doi.org/10.1073/pnas.102091699]
Walsh, V. L., Raviv, D., Dror, A. A., Shahin, H., Walsh, T., Kanaan, M. N., Avraham, K. B., King, M.-C. A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA. Mammalian Genome 22: 170-177, 2011. [PubMed: 21165622] [Full Text: https://doi.org/10.1007/s00335-010-9310-6]