HGNC Approved Gene Symbol: MYO3ACytogenetic location: 10p12.1 Genomic coordinates (GRCh38): 10:25,934,228-26,212,535 (from NCBI)▼ DescriptionActin-dependent ...
HGNC Approved Gene Symbol: MYO3A
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38): 10:25,934,228-26,212,535 (from NCBI)
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).
▼ Cloning and Expression
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.
▼ Gene Function
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.
▼ Molecular Genetics
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 is caused by 3 different recessive, loss of function mutations in myosin IIIA. 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.
▼ Animal Model
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.
▼ ALLELIC VARIANTS ( 3 Selected Examples):
.0001 DEAFNESS, AUTOSOMAL RECESSIVE 30
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 (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.
.0002 DEAFNESS, AUTOSOMAL RECESSIVE 30
MYO3A, IVS17, G-A, -12
See 606808.0001 and Walsh et al. (2002).
.0003 DEAFNESS, AUTOSOMAL RECESSIVE 30
MYO3A, IVS7, A-G, -2
See 606808.0001 and Walsh et al. (2002).