Whrn-flox Mouse

WHRN, also associated with DFNB31, is a gene encoding a cytoskeletal scaffold protein. It binds membrane protein complexes to the cytoskeleton in ocular photoreceptors and ear hair cell stereocilia. WHRN is part of the ankle-link complex (ALC), which is crucial for hair cell development [2,3,5]. Mutations in WHRN are linked to non-syndromic hearing loss and Usher syndrome type II, making it significant in understanding auditory and vestibular function and associated disorders [1,3,4].

In a Moroccan family with severe hearing loss, whole exome sequencing identified a homozygous mutation in WHRN (c.619G>T; p.Ala207Ser). Bioinformatics methods predicted pathogenic implications of this variation [3]. Adgrv1 Y6236fsX1 mutant mice, a model of a human deafness-associated mutation, showed that the Y6236fsX1 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, which regulates the ubiquitination and stability of USH2A, but this is disrupted in the mutant [2]. Also, different isoforms of WHRN (WHRN-L and WHRN-S) have distinct localizations within stereocilia and across hair cell types. Lack of both isoforms causes abnormally short stereocilia, profound deafness, and vestibular dysfunction, while WHRN-S alone can maintain some hair cell function [6].

In conclusion, WHRN plays a vital role in the development and function of ear hair cells and is associated with auditory and vestibular phenotypes. The study of WHRN through gene-based mouse models has provided insights into the mechanisms of hearing loss and Usher syndrome type II, highlighting its importance in understanding the pathophysiology of these diseases [2,3,6].