a mutation in synaptojanin 2 causes progressive hearing loss in the enu-mutagenised mouse strain mozartsynaptojanin 2的突变导致enu-mutagenised鼠标应变莫扎特进步听力损失.pdfVIP

A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain Mozart 1 1 1 3 4 Shehnaaz S. M. Manji , Louise H. Williams , Kerry A. Miller , Lisa M. Ooms , Melanie Bahlo , Christina A. Mitchell3, Hans-Henrik M. Dahl1,2* 1 Genetic Hearing Research, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia, 2 Department of Paediatrics, Melbourne University, Royal Children’s Hospital, Parkville, Victoria, Australia, 3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia, 4 Bioinformatics, Walter Eliza Hall Institute, Parkville, Victoria, Australia Abstract Background: Hearing impairment is the most common sensory impairment in humans, affecting 1:1,000 births. We have identified an ENU generated mouse mutant, Mozart, with recessively inherited, non-syndromic progressive hearing loss caused by a mutation in the synaptojanin 2 (Synj2), a central regulatory enzyme in the phosphoinositide-signaling cascade. Methodology/Principal Findings: The hearing loss in Mozart is caused by a p.Asn538Lys mutation in the catalytic domain of the inositol polyphosphate 5-phosphatase 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 (Synj2N538K/N538K) 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 c