Highlights•Hyperactivity associated with moderate hearing loss in ENU-induced whirlin mutant•Overexpression of C-terminus whirlin in the brain rescues hyperactive behaviors•Transcriptional profile of whirlin across tissues underscores pleiotropy•Qualitative deficit in the temporal processing of the acoustic stimulusSummaryDespite some evidence indicating diverse roles of whirlin in neurons, the functional corollary of whirlin gene function and behavior has not been investigated or broadly characterized. 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. Utilizing transgenics, we demonstrate rescue of the hyperactive phenotype and combined with the expression profiling data conclude whirlin plays an essential role in activity-related behaviors. These results highlight a pleiotropic role of whirlin within the brain and implicate alternative, central mediated pathways in its function.Graphical abstract

Pleiotropic brain function of whirlin identified by a novel mutation