Select autosomal dominant DFNA11 deafness variants activate Myo7A targeting in epithelial cells.

Myosin-7A (Myo7A) is a motor protein crucial for the organization and function of stereocilia, specialized actin-rich protrusions on the surface of inner ear hair cells that mediate hearing. Variants in Myo7A cause several forms of genetic hearing loss, including autosomal dominant DFNA11 deafness. Despite its importance, the structural elements that control Myo7A within cells are not well understood. In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells. Our findings reveal that the targeting of Myo7A is regulated by specific IQ motifs within its lever arm and that this regulation can function at least partially independent of its tail sequence. Importantly, we demonstrate that many of the DFNA11 deafness variants reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness.