Hearing loss in a whirlin mouse mutant is not reversed by activating the Whrn gene

WHRN gene mutations underlie several forms of deafness in humans and mice. It is not known whether WHRN-associated hearing loss can be reversed after its onset and we aimed to address this using a genetic approach. We show that a knockdown mouse allele of Whrn, Whrn^tm1a, caused reduced transcription of Whrn and early onset recessive hearing loss. A tamoxifen-inducible Flp recombinase (Flpo) was used to remove the transcription disruption cassette of the Whrn^tm1a allele (conversion to Whrn^tm1c) to allow expression of the Whrn gene after the onset of hearing loss. Tamoxifen administration at postnatal day 14 in Whrn^tm1a/tm1a mice carrying Flpo mice did not result in improved auditory brainstem response (ABR) thresholds at 4, 6 or 8 weeks old compared to Whrn^tm1a/tm1a mice without Flpo. This was also the case following tamoxifen administration at a younger age of 4 days old. Scanning electron microscopy revealed that this lack of hearing rescue was accompanied by irreversible defects in outer hair cell stereocilia. We propose that rescue of hearing loss caused by Whrn mutations is extremely challenging, particularly at translatable ages, likely due to developmental defects of stereocilia organisation which are not reversed by activating the Whrn gene.