Pleiotropic brain function of whirlin identified by a novel mutation

Despite some evidence indicating diverse roles of whirlin in neurons, the functional corollary of whirlin gene function and behaviour has not been investigated or broadly characterised. A single nucleotide variant was identified from our recessive ENU-mutagenesis screen at a donor-splice site in whirlin, a protein critical for proper sensorineural hearing function. The mutation (head-bob, hb) led to partial intron-retention causing a frameshift and introducing a premature termination codon. Mutant mice had a head-bobbing phenotype and significant hyperactivity across several phenotyping tests. Lack of complementation of head-bob with whirler mutant mice confirmed the head-bob mutation as functionally distinct with compound mutants having a mild-moderate hearing defect. Utilising transgenics, we demonstrate rescue of the hyperactive phenotype and combined with the expression profiling data conclude whirlin plays an essential role in activity-related behaviours. These results highlight a pleiotropic role of whirlin within the brain and implicates alternative, central mediated pathways in its function.