ABSTRACT
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.
Footnotes
Author contributions
Conceptualization: S.W.C.; Data curation: P.A., S.W.C.; Formal analysis: P.A., S.W.C.; Funding acquisition: B.J.P., S.W.C.; Investigation: P.A., G.T., X.L., S.M., M.J.G., S.Y.A., A.K.T., T.N., N.M.C., J.M., M.R.H., F.A.O., A.R., A.M., J.B., N.R., K.H., V.N., R.A., S.W.C.; Methodology: S.W.C.; Project administration: S.W.C.; Resources: S.W.C.; Supervision: B.J.P., S.W.C.; Validation: S.W.C.; Visualization: S.W.C.; Writing – original draft: S.W.C.; Writing – review & editing: P.A., S.W.C.
Funding
This work was supported by a University of Toledo Graduate Student Association Award (P.A.), Northern Ohio Alliances for Graduate Education and the Professoriate (NOA-AGEP) fellowship (M.J.G.), Undergraduate Summer Research and Creative Activities Program (USR-CAP), University of Toledo scholarships (A.K.T. and A.M.), University of Toledo Academic Year Research Awards (F.A., T.N. and J.M.), and National Institutes of Health awards R01DC015495 (B.J.P.), R15GM131382 and R15CA264735 (S.W.C.). Deposited in PMC for release after 12 months.
Data and resource availability
All relevant data and details of resources can be found within the article and its supplementary information.
