A humanized mouse model, demonstrating progressive hearing loss caused by MYO6 p.C442Y, is inherited in a semi-dominant pattern

Hear Res. 2019 Aug;379:79-88. doi: 10.1016/j.heares.2019.04.014. Epub 2019 Apr 26.


Myosin VI is an actin-associated molecular motor vital for auditory and vestibular function. It is encoded by MYO6 located on chromosome 6q13 in human. Pathogenic variants in MYO6 have been associated with both dominant and recessive forms of hearing loss. However, the molecular mechanisms remain unclear. We established a humanized knock-in mouse model, Myo6-C442Y, to mimic the p.C442Y missense variant identified in human patients with autosomal dominant nonsyndromic hearing loss designated as DFNA22. We characterized hearing and inner ear morphologies of Myo6-C442Y and wild-type control mice. We found that both homozygous and heterozygous Myo6-C442Y mice exhibited hearing loss from three weeks after birth that rapidly progressed to profound deafness by six to nine weeks of age. The hearing loss corresponded to the degeneration of hair cells in the organ of Corti. We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy. Additionally, hearing loss and inner-ear morphological anomalies were more pronounced and deteriorated more drastically in homozygous than in heterozygous Myo6-C442Y mice, indicating a semi-dominant inheritance pattern. Heterozygous Myo6-C442Y mice recapitulated the progressive postlingual sensorineural deafness in human, thus providing a useful model for elucidating the role myosin VI plays in the mammalian auditory system. Furthermore, the late-onset hearing loss of this mouse model may provide a therapeutic window for the emerging gene therapy, a promising strategy to treat certain forms of genetic deafness.

Keywords: Autosomal semi-dominant nonsyndromic hearing loss; Gene therapy; HCs; Hair cells; Mouse model; Myo6.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Auditory Threshold / physiology
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Genes, Dominant
  • Hair Cells, Auditory / pathology
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • Hearing Loss, Sensorineural / physiopathology
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Mutant Proteins / genetics*
  • Mutant Proteins / physiology
  • Mutation, Missense
  • Myosin Heavy Chains / genetics*
  • Myosin Heavy Chains / physiology
  • Stereocilia / pathology


  • Mutant Proteins
  • myosin VI
  • Myosin Heavy Chains

Supplementary concepts

  • Deafness, autosomal dominant nonsyndromic sensorineural 22