Whirlin has been reported to be involved in the formation of stereocilia within the inner ear and, provides a cytoskeletal scaffold for protein-protein interactions to occur. It is implicated in Usher Syndrome Type II, a leading cause of deafness and blindness, and considered to be an integral protein within the Usher interactome. However, much less is known about its function within other tissues and more recently evidence is emerging of its broader role within the nervous system.
Understanding the intrinsic function of whirlin has been complicated by alternative splicing events giving rise to multiple isoforms. We identified a novel point mutation in whirlin (head-bob) from an ENU-induced mouse mutagenesis screen, which disrupts the C-terminal isoforms. Characteristic head-bobbing and hyperactivity were observed at weaning indicating some neurological dysfunction. Phenotyping data strongly demonstrates a function for whirlin in activity-related behaviours that we were able to normalise using a BAC-transgenic line overexpressing wild-type C-terminal whirlin. This suggests that the C-terminal short isoform may be expressed more widely in neural tissue than has previously been reported. A mild deafness phenotype that was observed in these mutants was interestingly not rescued in the BAC-transgenic line. In parallel, the irregular shaped outer hair cell bundles found within the organ of Corti of mutants remained unchanged.
Our research has shed light on an alternative role for whirlin and reveals novel behavioural mechanisms suggesting a putative pleiotropic function for this protein in the mammalian system.