Transgene correction maintains normal cochlear structure and function in 6-month-old Myo15a mutant mice

The shaker2 (sh2) mouse is a murine model for human non-syndromic deafness DFNB3. The mice have abnormal circling behavior suggesting a balanced disorder, and profound deafness. The insertion of a bacterial artificial chromosome (BAC) transgene containing the Myo15a gene into sh2/sh2 zygotes confers hearing capability and abolishes the circling behavior in 1-month-old transgenic animals. In this study, we investigated both the hearing and the morphology of the cochlea in Myo15a mutants carrying this BAC transgene at two, four, or six months of age. The hearing threshold of these mice is normal, with no physiologically significant differences compared to age-matched heterozygous sh2J mice (with or without the BAC transgene). In six-month-old transgenic mice with the BAC, the morphology of hair cells in the apical and upper basal turns of the cochlea is normal. Hair cells of lower basal turn, however, were missing in some mutant animals. This study demonstrates that BAC transgene correction cannot only maintain normal morphology but also confer stable hearing function in Myo15a mutant mice for as long as 6 months. In addition, excess Myo15a expression has no physiologically significant protective or deleterious effects on hearing of normal mice, suggesting that the dosage of Myo15a may not be problematic for gene therapy.