Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing

  • Chang, Mun Young (Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine) ;
  • Kim, Ah Reum (Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine) ;
  • Kim, Nayoung K.D. (Samsung Genome Institute, Samsung Medical Center) ;
  • Lee, Chung (Samsung Genome Institute, Samsung Medical Center) ;
  • Lee, Kyoung Yeul (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology) ;
  • Jeon, Woo-Sung (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology) ;
  • Koo, Ja-Won (Department of Otorhinolaryngology, Seoul National University Bundang Hospital) ;
  • Oh, Seung Ha (Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine) ;
  • Park, Woong-Yang (Samsung Genome Institute, Samsung Medical Center) ;
  • Kim, Dongsup (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology) ;
  • Choi, Byung Yoon (Department of Otorhinolaryngology, Seoul National University Bundang Hospital)
  • Received : 2015.03.24
  • Accepted : 2015.06.11
  • Published : 2015.09.30


Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.


Supported by : Ministry of Health & Welfare


  1. Abecasis, G.R., Cherny, S.S., Cookson, W.O., and Cardon, L.R. (2001). GRR: graphical representation of relationship errors. Bioinformatics 17, 742-743.
  2. Bahler, M., and Rhoads, A. (2002). Calmodulin signaling via the IQ motif. FEBS Lett. 513, 107-113.
  3. Bashir, R., Fatima, A., and Naz, S. (2012). Prioritized sequencing of the second exon of MYO15A reveals a new mutation segregating in a Pakistani family with moderate to severe hearing loss. Eur. J. Med. Genet. 55, 99-102.
  4. Belguith, H., Aifa-Hmani, M., Dhouib, H., Said, M.B., Mosrati, M.A., Lahmar, I., Moalla, J., Charfeddine, I., Driss, N., Arab, S.B., et al. (2009). Screening of the DFNB3 locus: identification of three novel mutations of MYO15A associated with hearing loss and further suggestion for two distinctive genes on this locus. Genet. Test. Mol. Biomarkers 13, 147-151.
  5. Belyantseva, I.A., Boger, E.T., and Friedman, T.B. (2003). Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle. Proc. Natl. Acad. Sci. USA 100, 13958-13963.
  6. Belyantseva, I.A., Boger, E.T., Naz, S., Frolenkov, G.I., Sellers, J.R., Ahmed, Z.M., Griffith, A.J., and Friedman, T.B. (2005). Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat. Cell. Biol. 7, 148-156.
  7. Berg, J.S., Powell, B.C., and Cheney, R.E. (2001). A millennial myosin census. Mol. Biol. Cell. 12, 780-794.
  8. Besnard, T., Garcia-Garcia, G., Baux, D., Vache, C., Faugere, V., Larrieu, L., Leonard, S., Millan, J.M., Malcolm, S., Claustres, M., et al. (2014). Experience of targeted Usher exome sequencing as a clinical test. Mol. Genet. Genomic. Med. 2, 30-43.
  9. Bird, J.E., Takagi, Y., Billington, N., Strub, M.P., Sellers, J.R., and Friedman, T.B. (2014). Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking. Proc. Natl. Acad. Sci. USA 111, 12390-12395.
  10. Brownstein, Z., Friedman, L.M., Shahin, H., Oron-Karni, V., Kol, N., Abu Rayyan, A., Parzefall, T., Lev, D., Shalev, S., Frydman, M., et al. (2011). Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol. 12, R89.
  11. Cengiz, F.B., Duman, D., Sirmaci, A., Tokgoz-Yilmaz, S., Erbek, S., Ozturkmen-Akay, H., Incesulu, A., Edwards, Y.J., Ozdag, H., Liu, X.Z., et al. (2010). Recurrent and private MYO15A mutations are associated with deafness in the Turkish population. Genet. Test. Mol. Biomarkers 14, 543-550.
  12. Choi, B.Y., Park, G., Gim, J., Kim, A.R., Kim, B.J., Kim, H.S., Park, J.H., Park, T., Oh, S.H., Han, K.H., et al. (2013). Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. PLoS One 8, e68692.
  13. Cope, M.J., Whisstock, J., Rayment, I., and Kendrick-Jones, J. (1996). Conservation within the myosin motor domain: implications for structure and function. Structure 4, 969-987.
  14. Diaz-Horta, O., Duman, D., Foster, J., 2nd, Sirmaci, A., Gonzalez, M., Mahdieh, N., Fotouhi, N., Bonyadi, M., Cengiz, F.B., Menendez, I., et al. (2012). Whole-exome sequencing efficiently detects rare mutations in autosomal recessive nonsyndromic hearing loss. PLoS One 7, e50628.
  15. Donaudy, F., Ferrara, A., Esposito, L., Hertzano, R., Ben-David, O., Bell, R.E., Melchionda, S., Zelante, L., Avraham, K.B., and Gasparini, P. (2003). Multiple mutations of MYO1A, a cochlearexpressed gene, in sensorineural hearing loss. Am. J. Hum. Genet. 72, 1571-1577.
  16. Donaudy, F., Snoeckx, R., Pfister, M., Zenner, H.P., Blin, N., Di Stazio, M., Ferrara, A., Lanzara, C., Ficarella, R., Declau, F., et al. (2004). Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am. J. Hum. Genet. 74, 770-776.
  17. Duman, D., Sirmaci, A., Cengiz, F.B., Ozdag, H., and Tekin, M. (2011). Screening of 38 genes identifies mutations in 62% of families with nonsyndromic deafness in Turkey. Genet. Test. Mol. Biomarkers 15, 29-33.
  18. Eswar, N., Webb, B., Marti-Renom, M.A., Madhusudhan, M.S., Eramian, D., Shen, M.Y., Pieper, U., and Sali, A. (2006). Comparative protein structure modeling using Modeller. Curr. Protoc. Bioinformatics Chapter 5, Unit 5.6.
  19. Fattahi, Z., Shearer, A.E., Babanejad, M., Bazazzadegan, N., Almadani, S.N., Nikzat, N., Jalalvand, K., Arzhangi, S., Esteghamat, F., Abtahi, R., et al. (2012). Screening for MYO15A gene mutations in autosomal recessive nonsyndromic, GJB2 negative Iranian deaf population. Am. J. Med. Genet. A 158a, 1857-1864.
  20. Friedman, T.B., Liang, Y., Weber, J.L., Hinnant, J.T., Barber, T.D., Winata, S., Arhya, I.N., and Asher, J.H., Jr. (1995). A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat. Genet. 9, 86-91.
  21. Friedman, T.B., Sellers, J.R., and Avraham, K.B. (1999). Unconventional myosins and the genetics of hearing loss. Am. J. Med. Genet. 89, 147-157.<147::AID-AJMG5>3.0.CO;2-6
  22. Friedman, T.B., Hinnant, J.T., Ghosh, M., Boger, E.T., Riazuddin, S., Lupski, J.R., Potocki, L., and Wilcox, E.R. (2002). DFNB3, spectrum of MYO15A recessive mutant alleles and an emerging genotype-phenotype correlation. Adv. Otorhinolaryngol. 61, 124-130.
  23. Gao, X., Zhu, Q.Y., Song, Y.S., Wang, G.J., Yuan, Y.Y., Xin, F., Huang, S.S., Kang, D.Y., Han, M.Y., Guan, L.P., et al. (2013). Novel compound heterozygous mutations in the MYO15A gene in autosomal recessive hearing loss identified by whole-exome sequencing. J. Transl. Med. 11, 284.
  24. Garcia-Alvarez, B., de Pereda, J.M., Calderwood, D.A., Ulmer, T.S., Critchley, D., Campbell, I.D., Ginsberg, M.H., and Liddington, R.C. (2003). Structural determinants of integrin recognition by talin. Mol. Cell. 11, 49-58.
  25. Hilgert, N., Smith, R.J., and Van Camp, G. (2009). Function and expression pattern of nonsyndromic deafness genes. Curr. Mol. Med. 9, 546-564.
  26. Kalay, E., Uzumcu, A., Krieger, E., Caylan, R., Uyguner, O., Ulubil-Emiroglu, M., Erdol, H., Kayserili, H., Hafiz, G., Baserer, N., et al. (2007). MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation. Am. J. Med. Genet. A 143a, 2382-2389.
  27. Kim, H.Y., Rhim, T., Ahnm M.H., Yoon, P.O., Kim, S.H., Lee, S.H., and Park, C.S. (2008). The fast skeletal muscle myosin light chain is differentially expressed in smooth muscle cells of OVAchallenged mouse trachea. Mol. Cells 25, 78-85.
  28. Krendel, M., and Mooseker, M.S. (2005). Myosins: tails (and heads) of functional diversity. Physiology (Bethesda) 20, 239-251.
  29. Lalwani, A.K., Goldstein, J.A., Kelley, M.J., Luxford, W., Castelein, C.M., and Mhatre, A.N. (2000). Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet. 67, 1121-1128.
  30. Liang, Y., Wang, A., Probst, F.J., Arhya, I.N., Barber, T.D., Chen, K.S., Deshmukh, D., Dolan, D.F., Hinnant, J.T., Carter, L.E., et al. (1998). Genetic mapping refines DFNB3 to 17p11.2, suggests multiple alleles of DFNB3, and supports homology to the mouse model shaker-2. Am. J. Hum. Genet. 62, 904-915.
  31. 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., et al. (1999). Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2. Genomics 61, 243-258.
  32. Liburd, N., Ghosh, M., Riazuddin, S., Naz, S., Khan, S., Ahmed, Z., Riazuddin, S., Liang, Y., Menon, P.S., Smith, T., et al. (2001). 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.
  33. Mooseker, M.S., and Cheney, R.E. (1995). Unconventional myosins. Annu. Rev. Cell. Dev. Biol. 11, 633-675.
  34. Nal, N., Ahmed, Z.M., Erkal, E., Alper, O.M., Luleci, G., Dinc, O., Waryah, A.M., Ain, Q., Tasneem, S., Husnain, T., et al. (2007). Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing. Hum. Mutat. 28, 1014-1019.
  35. Park, J.H., Kim, N.K.D., Kim, A.R., Rhee, J., Oh, S.H., Koo, J.W., Nam, J.Y., Park, W.Y., and Choi, B.Y. (2014). Comprehensive exploration of molecular genetic etiology for cochlear implantees with severe to profound hearing loss and its implication. orphanet. J. Rare Dis. 9, 167
  36. 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., et al. (1998). Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280, 1444-1447.
  37. Shearer, A.E., Hildebrand, M.S., Webster, J.A., Kahrizi, K., Meyer, N.C., Jalalvand, K., Arzhanginy, S., Kimberling, W.J., Stephan, D., Bahlo, M., et al. (2009). Mutations in the first MyTH4 domain of MYO15A are a common cause of DFNB3 hearing loss. Laryngoscope 119, 727-733.
  38. Tilney, L.G., and Tilney, M.S. (1986). Functional organization of the cytoskeleton. Hear. Res. 22, 55-77.
  39. Tilney, L.G., Tilney, M.S., and DeRosier, D.J. (1992). Actin filaments, stereocilia, and hair cells: how cells count and measure. Annu. Rev. Cell. Biol. 8, 257-274.
  40. Walsh, T., Walsh, V., Vreugde, S., Hertzano, R., Shahin, H., Haika, S., Lee, M.K., Kanaan, M., King, M.C., and Avraham, K.B., (2002). From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc. Natl. Acad. Sci. USA 99, 7518-7523.
  41. 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., et al. (1998). Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280, 1447-1451.
  42. Woo, H.M., Park, H.J., Baek, J.I., Park, M.H., Kim, U.K., Sagong, B., and Koo, S.K. (2013). Whole-exome sequencing identifies MYO15A mutations as a cause of autosomal recessive nonsyndromic hearing loss in Korean families. BMC Med. Genet. 14, 72.
  43. Yang, T., Wei, X., Chai, Y., Li, L., and Wu, H. (2013). Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet. J. Rare Dis. 8, 85.

Cited by

  1. MYO15A splicing mutations in hearing loss: A review literature and report of a novel mutation vol.96, 2017,
  2. Homozygous mutations in PJVK and MYO15A genes associated with non-syndromic hearing loss in Moroccan families vol.101, 2017,
  3. Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation vol.23, pp.8, 2016,
  4. Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans vol.11, pp.10, 2016,
  5. Establishment of a Flexible Real-Time Polymerase Chain Reaction-Based Platform for Detecting Prevalent Deafness Mutations Associated with Variable Degree of Sensorineural Hearing Loss in Koreans vol.11, pp.9, 2016,
  6. An update of common autosomal recessive non-syndromic hearing loss genes in Iranian population vol.97, 2017,
  7. Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness vol.37, pp.10, 2016,
  8. Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness vol.19, pp.1, 2018,
  9. Mutations Identified in One Chinese Family with Autosomal Recessive Nonsyndromic Hearing Loss vol.2018, pp.1687-5443, 2018,