Haploinsufficiency of Whrn Contributes to Progressive Sensorineural Hearing Loss in C57BL6 Mice.

Purpose: Whrn, encoding whirlin, is one of the genes highly relevant to Usher syndrome (USH) that has been known as an autosomal recessive genetic disorder that is characterized with sensorineural hearing loss with retinitis pigmentosa. Although recent studies on the other USH genes, PDZD7 and Ush1 g, showed a possibility of haploinsufficiency effect, the potential contribution of heterozygous Whrn loss to hearing loss remains unclear.

Methods: To investigate the effect of Whrn haploinsufficiency, we conducted a longitudinal study assessing auditory function in heterozygous Whrn mutant (Whrn^+/-) mice in which long isoform of Whrn was deleted by replacing exon 1 with Neo cassette without disturbing short isoform. The threshold of auditory brainstem responses (ABRs) was measured on 135 Whrn^+/- mice and littermate 133 wild-type (WT) mice from 1 to 6 months of ages. From those data, the threshold from male and female were separately analyzed to investigate sex-dependent effect. To further investigate underlie mechanisms, hair cell death was investigated using immunohistostaining from 4 to 5 WT, 5 female Whrn^+/-, and 7 male Whrn^+/- mice at 4-5 months old.

Results: Hearing threshold was significantly increased with aging in Whrn^+/- mice compared to WT controls. Both WT and Whrn^+/- mice exhibited sex-dependent variations in hearing sensitivity. Notably, Whrn^+/- males showed a progressive hearing loss with age, while Whrn^+/- females exhibited elevated hearing thresholds as early as 1-2 month of age compared to WT females.

Conclusion: These results provide evidence for a haploinsufficiency effect of Whrn on auditory function and highlight its potential role in progressive sensorineural hearing loss.