Whrn-KO Mouse

Whrn, a gene encoding a cytoskeletal scaffold protein, is crucial as it binds membrane protein complexes to the cytoskeleton in ocular photoreceptors and ear hair cell stereocilia [2]. It is part of the ankle-link complex (ALC) along with USH2A, PDZD7, and ADGRV1, which is essential for hair cell development [1,3]. Mutations in Whrn are associated with non-syndromic hearing loss and Usher syndrome type II [2].

In Adgrv1 Y6236fsX1 mutant mice (a model for human deafness-associated mutation), the mutation disrupts the interaction between ADGRV1 and other ALC components including Whrn, leading to stereocilia disorganization and mechanoelectrical transduction deficits. ADGRV1 normally inhibits Whrn phosphorylation through regional cAMP-PKA signaling, regulating USH2A ubiquitination and stability, but the mutant ADGRV1 Y6236fsX1 fails to do so [1]. Also, different isoforms of Whrn (long and short) have distinct localizations within stereocilia and across hair cell types. Lack of both isoforms in mutants causes abnormally short stereocilia, profound deafness, and vestibular dysfunction, while the short isoform alone can maintain some auditory response and no overt vestibular dysfunction [4].

In conclusion, Whrn plays a vital role in the development and function of hair cells in the inner ear and in maintaining the structure of ocular photoreceptors. Studies using mouse models have revealed its significance in processes related to hearing and vision, with mutations in Whrn being linked to Usher syndrome type II and non-syndromic hearing loss, providing insights into the disease mechanisms and potential therapeutic targets.