a mutation in synaptojanin 2 causes progressive hearing loss in the enumutagenised mouse strain mozart background hearing impairment is the most common sensory impairment in humans affecting 11000 births we have identified an enu generated mouse mutant mozart with recessively inherited nonsyndromic progressive hearing loss caused by a mutation in the synaptojanin 2 synj2 a central regulatory enzyme in the phosphoinositidesignaling cascademethodologyprincipal findings the hearing loss in mozart is caused by a pasn538lys mutation in the catalytic domain of the inositol polyphosphate 5phosphatase synaptojanin 2 within the cochlea synj2 mrna expression was detected in the inner and outer hair cells but not in the spiral ganglion synj2n538k mutant protein showed loss of lipid phosphatase activity and was unable to degrade phosphoinositide signaling molecules mutant mozart mice synj2n538kn538k exhibited progressive hearing loss and showed signs of hair cell degeneration as early as two weeks of age with fusion of stereocilia followed by complete loss of hair bundles and ultimately loss of hair cells no changes in vestibular or neurological function or other clinical or behavioral manifestations were apparentconclusionssignificance phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death proliferation actin polymerization and ion channel activity these results reveal synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function