Correction of Deafness in <i>shaker-2</i> Mice by an Unconventional Myosin in a BAC Transgene

TLDR

The shaker‑2 mouse mutation, homologous to human DFNB3, causes deafness and circling behavior. A BAC transgene from the shaker‑2 critical region corrected vestibular defects, deafness, and inner ear morphology in shaker‑2 mice. Sequencing of the BAC identified the unconventional myosin Myo15, which carries a conserved motor‑domain substitution in shaker‑2 mice; its loss causes shortened stereocilia, abnormal actin protrusions, and disrupted actin organization in cochlear hair cells, accounting for the deafness.

Abstract

The shaker-2 mouse mutation, the homolog of human DFNB3 , causes deafness and circling behavior. A bacterial artificial chromosome (BAC) transgene from the shaker-2 critical region corrected the vestibular defects, deafness, and inner ear morphology of shaker-2 mice. An unconventional myosin gene, Myo15 , was discovered by DNA sequencing of this BAC. Shaker-2 mice were found to have an amino acid substitution at a highly conserved position within the motor domain of this myosin. Auditory hair cells of shaker-2 mice have very short stereocilia and a long actin-containing protrusion extending from their basal end. This histopathology suggests that Myo15 is necessary for actin organization in the hair cells of the cochlea.