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Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of  Kiaa1024L / Minar2 , a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of  kiaa1024L/minar2  causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the  kiaa1024L/minar2  mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of  kiaa1024L/minar2  reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the  kiaa1024L/minar2  mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.

Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles