Limited Potential to Reverse Deafness Caused by Mutation of Myo7a.

PURPOSE: MYO7A is involved in several forms of deafness in humans and mice, and in this study we aimed to investigate if the hearing loss could be reversed after its onset.

METHODS

A knockdown allele of Myo7a in the mouse, Myo7atm1a, was characterised by recording ABR thresholds at ages from 4 weeks to 6 months old and measuring the amount of hair cell degeneration at 4 weeks old. Scanning electron microscopy was used to assess the condition of stereocilia bundles. A tamoxifen-inducible Flp recombinase was used to activate expression of Myo7a in Myo7atm1a/tm1a homozygotes at 4 weeks old by excising the transcription disruption cassette in the tm1a allele allowing expression of the Myo7a gene, and ABRs were recorded before and after activation of the gene.

RESULTS

Myo7atm1a was found to be a recessive allele causing reduced transcription and early onset profound deafness. Some hair cell loss was found at 4 weeks old, and scanning electron microscopy showed Myo7atm1a severely affects stereocilia morphology and organisation. Activation of Myo7a expression at 4 weeks old results in very small improvements in ABR thresholds of Myo7atm1a/tm1a mice at 12 and 18 kHz at 6 and 8 weeks old but there were no responses to sound by 14 weeks old.

CONCLUSIONS

It is likely to be challenging to reverse hearing loss due to very early developmental defects of stereocilia organisation.