Key result
The D179Y missense mutation in myosin VI disrupts motor function and head coordination, leading to mislocalization of kinocilia, branching of stereocilia, and ultimately deafness in mice.
The D179Y mutation in myosin VI disrupts motor function and coordination between myosin heads, revealing its essential role in the structural integrity of inner ear hair cells and hearing.
Supports myosin VI's role in hair cell integrity in mice; hypothesis-generating for genetic deafness mechanisms before human translation.
Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or 'gating' in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI-impaired hair cells, and ultimately leading to deafness.
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Hertzano et al. (2008) studied Deafness and vestibular dysfunction. Myo6 D179Y mutation vs. Wild type was evaluated on Myosin VI motor function and stereocilia morphology. The D179Y missense mutation in myosin VI disrupts motor function and head coordination, leading to mislocalization of kinocilia, branching of stereocilia, and ultimately deafness in mice.