Alternative titles; symbols
HGNC Approved Gene Symbol: MYO15A
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:18,108,756-18,179,800 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p11.2 | Deafness, autosomal recessive 3 | 600316 | Autosomal recessive | 3 |
Wang et al. (1998) isolated a partial MYO15A cDNA from a human chromosome 17-specific human cDNA library. The deduced 1,585-amino acid partial protein shares 99% amino acid identity with a mouse partial protein isolated by Probst et al. (1998). MYO15A contains an N-terminal motor domain, 2 light-chain binding IQ motifs, and a tail region containing a MyTH4 and a talin (186745)-like domain. The extent of sequence divergence of the MYO15A motor domain from other reported myosins qualified MYO15A as a new branch of the myosin superfamily. Northern blot analysis detected MYO15A expression in human fetal and adult brain, and RT-PCR analysis detected expression in human fetal cochlea. RNA dot-blot analysis showed expression in ovary, testis, kidney, and pituitary gland.
Probst et al. (1998) isolated a partial mouse Myo15a clone. Northern blot analysis detected Myo15a in adult mouse brain and kidney.
Liang et al. (1999) characterized the complete MYO15A sequence. The 3,530-residue protein has a calculated molecular mass of 395 kD. The corresponding mouse protein contains 3,511 residues and shares 82% overall identity. A full-length 11.9-kb mRNA, not including the poly(A) tail, was detected. The MYO15A protein sequence was found to be unusual for myosins in that it contains a 1,200-residue N-terminal extension, encoded by exon 2, that precedes the conserved motor domain. Several alternatively spliced transcripts were identified in both species, including 1 transcript that skipped exon 2. There was high expression in the adult pituitary gland.
Belyantseva et al. (2005) noted that the C terminus of MYO15A contains 2 repeats each composed of a MyTH4 and a FERM domain, separated by an SH3 domain, with a PDZ ligand at the C-terminal tip.
Belyantseva et al. (2005) determined that the C-terminal PDZ ligand of mouse Myo15a interacted with the third PDZ domain of whirlin (WHRN; 607928), and this interaction was required for the targeting of whirlin to the tips of stereocilia. Reintroduction of Myo15a into hair cells of Myo15a-deficient mice restored the recruitment of endogenous whirlin to the tips of stereocilia. Belyantseva et al. (2005) concluded that the interaction of MYO15A with whirlin is a key event in hair bundle morphogenesis.
Delprat et al. (2005) showed that whirlin, like myosin XVa, is present at the very tip of rat stereocilium in the developing and mature hair bundles of the cochlear and vestibular system. The myosin XVa SH3-MyTH4 region bound to the short isoform of whirlin (PR-PDZ3), whereas the C-terminal MyTH4-FERM region of myosin XVa bound to the PDZ1 and PDZ2 domains of the long whirlin isoform. Delprat et al. (2005) concluded that a direct myosin XVa/whirlin interaction at the stereocilia tip is likely to control the elongation of stereocilia.
Manor et al. (2011) determined that Myo15a and whirlin interacted with Eps8 (600206) at the tips of stereocilia in mouse inner and outer cochlear and vestibular hair cells. Knockout of Eps8, like knockout of Myo15a and whirlin, caused shortening of stereocilia and profound deafness. Knockdown studies showed that Eps8 was dependent upon Myo15a for its stereocilia localization. Knockdown of whirlin reduced expression of both Myo15a and Eps8 at stereocilia tips. Overexpression of Eps8 with Myo15a resulted in stereocilia elongation. In transfected COS-7 cells, Myo15a and Eps8 expression cooperatively elongated actin protrusions. Protein pull-down experiments with truncated proteins revealed that the second MyTh4-FERM domain of the Myo15a tail interacted predominantly with the C terminus of Eps8. The N terminus of Eps8 interacted with whirlin.
Liang et al. (1999) determined that the MYO15A gene contains 66 exons and spans about 71 kb.
In affected individuals from 3 unrelated families with autosomal recessive congenital deafness (DFNB3; 600316), Wang et al. (1998) identified homozygous mutations in the MYO15A gene (602666.0001-602666.0003).
In 3 consanguineous families from Pakistan and India with DFNB3, Liburd et al. (2001) identified homozygous mutations in the MYO15A gene (602666.0004-602666.0006). In addition, a hemizygous missense mutation (602666.0007) was found in a patient with Smith-Magenis syndrome (182290) due to a deletion in chromosome 17p11.2. The patient had moderately severe hearing loss. The unaffected mother was heterozygous for the mutation.
Nal et al. (2007) identified 16 novel MYO15A mutations that cosegregated with DFNB3 hearing loss in 20 families from Turkey, India, and Pakistan. Two mutations (E1105X; 602666.0008 and 3334delG; 602666.0009) were located in the alternatively-spliced exon 2 that encodes the large N-terminal extension of the MYO15A protein. The findings indicated that the long isoform of MYO15A is necessary for normal auditory function.
In a large multigenerational consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness, negative for mutations in the deafness-associated GJB2 (121011) and GJB6 (604418) genes and for the A1555G mitochondrial mutation in the MTRNR1 gene (561000.0001), Lezirovitz et al. (2008) identified unexpected genetic heterogeneity: 15 affected individuals from 'branch 2' of the family were homozygous for a 1-bp deletion (10573delA; 602666.0012) in the MYO15A gene, whereas 4 affected sibs from 'branch 1' and 1 individual from 'branch 2' were compound heterozygous for 10573delA and a 4-bp deletion (602666.0013) in MYO15A. In 1 patient, only the 10573delA mutation could be identified. No mutations in MYO15A were identified in 5 patients from 2 additional branches of the family.
Shaker-2 (sh2) is a recessive mouse mutation on chromosome 11 that arose in the progeny of an x-ray irradiated mouse. Affected mice lack a normal startle response to sound and show no auditory brainstem responses to sound pressure levels up to high levels, indicating profound deafness. Associated vestibular defects cause head-tossing and circling behavior. The stereociliary bundles on both the inner and outer hair cells of 1-month-old shaker-2 mice are short and dysmorphic, but are arrayed in a nearly normal pattern. Complete 1-Mb yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC) contigs that spanned the shaker-2 critical region were generated. Probst et al. (1998) used a BAC transgene from the shaker-2 critical region to correct the vestibular defects, deafness, and inner ear morphology of shaker-2 mice. Using this approach, the authors identified an unconventional myosin gene, designated Myo15. Shaker-2 mice were found to have an amino acid substitution at a highly conserved position within the motor domain of this myosin. Auditory hair cells of shaker-2 mice have very short stereocilia and a long actin-containing protrusion extending from the basal end. This histopathology suggested that Myo15 is necessary for actin organization in the hair cells of the cochlea.
Anderson et al. (2000) described the shaker-2(J) lesion, which is a 14.7-kb deletion that removes the last 6 exons from the 3-prime terminus of the Myo15 transcript. These exons encode a FERM (F, ezrin, radixin, and moesin) domain that may interact with integral membrane proteins. Despite the deletion of 6 exons, in situ hybridization revealed that Myo15 mRNA transcripts and protein were present in the postnatal day 1 shaker-2J inner ear, suggesting that the FERM domain is critical for the development of normal hearing and balance. Myo15 transcripts were first detectable at embryonic day 13.5 in wildtype mice. Myo15 transcripts in the mouse inner ear were restricted to the sensory epithelium of the developing cristae ampularis, macula utriculi, and macula sacculi of the vestibular system, as well as to the developing organ of Corti. Similar to shaker-2, shaker-2J alleles result in abnormally short hair cell stereocilia in the cochlear and vestibular systems. The authors suggested that Myo15 may be important for both the structure and function of these sensory epithelia.
The MYO15, MYO6 (600970), and MYO7A (276903) genes are essential for hearing in both humans and mice. Despite widespread expression, homozygosity for mutations in these genes only results in auditory or ocular dysfunction. The pirouette (pi) mouse exhibits deafness and inner ear pathology resembling that of Myo15 mutant mice. Karolyi et al. (2003) crossed shaker-2 mice to Myo6, Myo7a, and pi mutant mouse strains. Viable double-mutant homozygotes were obtained from each cross, and hearing in doubly heterozygous mice was similar to singly heterozygous mice. All critical cell types of the cochlear sensory epithelium were present in double-mutant mice, and cochlear stereocilia exhibited a superimposition of single-mutant phenotypes. Karolyi et al. (2003) suggested that the function of Myo15 is distinct from that of Myo6, Myo7a, or pi in development and/or maintenance of stereocilia.
In affected individuals with recessive congenital deafness (DFNB3; 600316) from a kindred in Bengkala, an Indonesian village on the north shore of Bali, Wang et al. (1998) found homozygosity for an ile892-to-phe (I892F) mutation in the MYO15 gene.
Friedman et al. (1995) had reported that 2% of the residents of Bengkala had DFNB3. The remote village dated to at least the 13th century as documented by charters inscribed in Sanskrit on metallic plates. Of the 2,185 residents, 47 had profound deafness of the type described as DFNB3. As an adaptation to the high percentage of deaf individuals, the citizens of Bengkala had developed a unique sign language used by most of the hearing persons as well as the deaf villagers. Deaf couples produced all deaf progeny. In 4- and 5-generation Bengkala kindreds, 2 of which were illustrated, there were no consanguineous marriages.
In a consanguineous Indian family, Wang et al. (1998) found that individuals with congenital deafness (DFNB3; 600316) were homozygous for an asn890-to-tyr (N890Y) missense mutation in the MYO15 gene.
In a consanguineous Indian family, Wang et al. (1998) found that individuals with congenital deafness (DFNB3; 600316) carried a lys1300-to-ter (K1300X) nonsense mutation in the MYO15 gene.
In profoundly deaf (DFNB3; 600316) members of a Pakistani family, Liburd et al. (2001) found a homozygous C-to-T transition at nucleotide 4023 in exon 3 of the MYO15A gene, resulting in a gln1229-to-ter (Q1229X) substitution.
In a consanguineous Pakistani family, Liburd et al. (2001) found that deaf (DFNB3; 600316) members had a homozygous splice donor site mutation in the MYO15A gene, IVS4+1G-T.
In a consanguineous Pakistani family, Liburd et al. (2001) found that 3 deaf (DFNB3; 600316) sibs were homozygous for a G-to-T transversion at nucleotide 8486 in exon 44 of the MYO15A gene, resulting in a gln2716-to-his (Q2716H) substitution.
In 1 of 8 patients from North America with Smith-Magenis syndrome (SMS; 182290) due to deletion in 17p11.2, Liburd et al. (2001) found that moderately severe sensorineural hearing loss (DFNB3; 600316) was associated with hemizygosity for a C-to-T transition at nucleotide 6952 of the MYO15A gene, resulting in a thr2205-to-ile (T2205I) substitution. The mother, who had normal hearing, was heterozygous for T2205I. Thus, the SMS deletion in this patient appeared to have occurred in a gamete from the father.
In affected members of a consanguineous Pakistani family with DFNB3 (600316), Nal et al. (2007) identified a homozygous 3313G-T transversion in exon 2 of the MYO15A gene, resulting in a glu1105-to-ter (E1105X) substitution in the long N-terminal extension.
In affected members of a consanguineous Pakistani family with DFNB3 (600316), Nal et al. (2007) identified a homozygous 1-bp deletion (3334delG) in exon 2 of the MYO15A gene, resulting in a frameshift and premature protein truncation.
In affected members of a consanguineous Turkish family with DFNB3 (600316), Kalay et al. (2007) identified a homozygous G-to-T transversion at nucleotide 5492 in exon 21 of the MYO15A gene, resulting in a gly1831-to-val (G1831V) substitution in the motor domain of the protein.
In affected members of a consanguineous Turkish family with DFNB3 (600316), Kalay et al. (2007) identified a homozygous G-to-C transversion affecting the acceptor site of intron 50 (-1G-C). Computational splice site analysis of the variant predicted that the splice acceptor site of intron 50 is destroyed.
In 15 members of a large consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness (600316), Lezirovitz et al. (2008) identified homozygosity for a 1-bp deletion (10573delA) in exon 66 of the MYO15A gene, causing a frameshift that was predicted to eliminate the last 6 amino acids at the C terminus, including the class 1 PDZ binding ligand, and to abolish the natural stop codon, thus leading to the addition of 28 novel amino acids. In another affected individual from the same branch of the family, only a single mutated 10573delA allele could be identified. Another 5 affected individuals were found to be compound heterozygous for 10573delA and a 4-bp deletion in the MYO15A gene (602666.0013).
In 5 members of a large consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness (600316), Lezirovitz et al. (2008) identified compound heterozygosity for 10573delA (602666.0012) and a 4-bp deletion (9957delTGAC) in exon 62 of the MYO15A gene, predicted to cause a premature stop codon that would eliminate 211 amino acids from the C terminus, including approximately half of the second FERM domain and the entire class 1 PDZ ligand.
Anderson, D. W., Probst, F. J., Belyantseva, I. A., Fridell, R. A., Beyer, L., Martin, D. M., Wu, D., Kachar, B., Friedman, T. B., Raphael, Y., Camper, S. A. The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells. Hum. Molec. Genet. 9: 1729-1738, 2000. [PubMed: 10915760] [Full Text: https://doi.org/10.1093/hmg/9.12.1729]
Belyantseva, I. A., Boger, E. T., Naz, S., Frolenkov, G. I., Sellers, J. R., Ahmed, Z. M., Griffith, A. J., Friedman, T. B. Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nature Cell Biol. 7: 148-156, 2005. [PubMed: 15654330] [Full Text: https://doi.org/10.1038/ncb1219]
Delprat, B., Michel, V., Goodyear, R., Yamasaki, Y., Michalski, N., El-Amraoui, A., Perfettini, I., Legrain, P., Richardson, G., Hardelin, J.-P., Petit, C. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly. Hum. Molec. Genet. 14: 401-410, 2005. [PubMed: 15590698] [Full Text: https://doi.org/10.1093/hmg/ddi036]
Friedman, T. B., Liang, Y., Weber, J. L., Hinnant, J. T., Barber, T. D., Winata, S., Arhya, I. N., Asher, J. H., Jr. A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nature Genet. 9: 86-91, 1995. [PubMed: 7704031] [Full Text: https://doi.org/10.1038/ng0195-86]
Kalay, E., Uzumcu, A., Krieger, E., Caylan, R., Uyguner, O., Ulubil-Emiroglu, M., Erdol, H., Kayserili, H., Hafiz, G., Baserer, N., Heister, A. J. G. M., Hennies, H. C., Nurnberg, P., Basaran, S., Brunner, H. G., Cremers, C. W. R. J., Karaguzel, A., Wollnik, B., Kremer, H. MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation. Am. J. Med. Genet. 143A: 2382-2389, 2007. [PubMed: 17853461] [Full Text: https://doi.org/10.1002/ajmg.a.31937]
Karolyi, I. J., Probst, F. J., Beyer, L., Odeh, H., Dootz, G., Cha, K. B., Martin, D. M., Avraham, K. B., Kohrman, D., Dolan, D. F., Raphael, Y., Camper, S. A. Myo15 function is distinct from Myo6, Myo7a and pirouette genes in development of cochlear stereocilia. Hum. Molec. Genet. 12: 2797-2805, 2003. [PubMed: 12966030] [Full Text: https://doi.org/10.1093/hmg/ddg308]
Lezirovitz, K., Pardono, E., de Mello Auricchio, M. T. B., de Carvalho e Silva, F. L., Lopes, J. J., Abreu-Silva, R. S., Romanos, J., Batissoco, A. C., Mingroni-Netto, R. C. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness. Europ. J. Hum. Genet. 16: 89-96, 2008. Note: Erratum: Europ. J. Hum. Genet. 16: 660 only, 2008. [PubMed: 17851452] [Full Text: https://doi.org/10.1038/sj.ejhg.5201917]
Liang, Y., Wang, A., Belyantseva, I. A., Anderson, D. W., Probst, F. J., Barber, T. D., Miller, W., Touchman, J. W., Jin, L., Sullivan, S. L., Sellers, J. R., Camper, S. A., Lloyd, R. V., Kacher, B., Friedman, T. B., Fridell, R. A. Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2. Genomics 61: 243-258, 1999. [PubMed: 10552926] [Full Text: https://doi.org/10.1006/geno.1999.5976]
Liburd, N., Ghosh, M., Riazuddin, S., Naz, S., Khan, S., Ahmed, Z., Riazuddin, S., Liang, Y., Menon, P. S. N., Smith, T., Smith, A. C. M., Chen, K.-S., Lupski, J. R., Wilcox, E. R., Potocki, L., Friedman, T. B. Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum. Genet. 109: 535-541, 2001. [PubMed: 11735029] [Full Text: https://doi.org/10.1007/s004390100604]
Manor, U., Disanza, A., Grati, M'H., Andrade, L., Lin, H., Di Fiore, P. P., Scita, G., Kachar, B. Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Curr. Biol. 21: 167-172, 2011. [PubMed: 21236676] [Full Text: https://doi.org/10.1016/j.cub.2010.12.046]
Nal, N., Ahmed, Z. M., Erkal, E., Alper, O. M., Luleci, G., Dinc, O., Waryah, A. M., Ain, Q., Tasneem, S., Husnain, T., Chattaraj, P., Riazuddin, S., Boger, E., Ghosh, M., Kabra, M., Riazuddin, S., Morell, R. J., Friedman, T. B. Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing. Hum. Mutat. 28: 1014-1019, 2007. [PubMed: 17546645] [Full Text: https://doi.org/10.1002/humu.20556]
Probst, F. J., Fridell, R. A., Raphael, Y., Saunders, T. L., Wang, A., Liang, Y., Morell, R. J., Touchman, J. W., Lyons, R. H., Noben-Trauth, K., Friedman, T. B., Camper, S. A. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280: 1444-1447, 1998. [PubMed: 9603735] [Full Text: https://doi.org/10.1126/science.280.5368.1444]
Wang, A., Liang, Y., Fridell, R. A., Probst, F. J., Wilcox, E. R., Touchman, J. W., Morton, C. C., Morell, R. J., Noben-Trauth, K., Camper, S. A., Friedman, T. B. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280: 1447-1451, 1998. [PubMed: 9603736] [Full Text: https://doi.org/10.1126/science.280.5368.1447]