Whrn-KO Mouse

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

In a study establishing Adgrv1 Y6236fsX1 mutant mice as a model for a deafness-associated human mutation, it was shown that the mutation disrupts the interaction between ADGRV1 and other ALC components, including WHRN. ADGRV1 normally inhibits WHRN phosphorylation through regional cAMP-PKA signaling, which in turn regulates the ubiquitination and stability of USH2A. The mutant ADGRV1 fails to do so, leading to stereocilia disorganization and mechanoelectrical transduction deficits [1]. Also, in a Moroccan family, whole exome sequencing identified a homozygous WHRN gene variant (c.619G > T; p.Ala207Ser) in a patient with severe hearing loss, and bioinformatics methods predicted the pathogenic implications of this variation [2].

In conclusion, WHRN is essential for the proper functioning of the ankle-link complex in hair cell development. Studies using mouse models have revealed its role in maintaining the stability of ALC components and normal stereocilia function, with implications for understanding the pathogenesis of hearing-related diseases such as Usher syndrome and non-syndromic hearing loss [1,2].

References:

1. Guan, Ying, Du, Hai-Bo, Yang, Zhao, Sun, Jin-Peng, Xu, Zhi-Gang. 2023. Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2205993. doi:10.1002/advs.202205993. https://pubmed.ncbi.nlm.nih.gov/37066759/

2. AitRaise, Imane, Amalou, Ghita, Redouane, Salaheddine, Petit, Christine, Barakat, Abdelhamid. 2023. Novel pathogenic WHRN variant causing hearing loss in a moroccan family. In Molecular biology reports, 50, 10663-10669. doi:10.1007/s11033-023-08901-8. https://pubmed.ncbi.nlm.nih.gov/37924449/

3. Wang, Huang, Du, Haibo, Ren, Rui, Xu, Zhigang, Lu, Qing. 2023. Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation. In Nature communications, 14, 1657. doi:10.1038/s41467-023-37267-5. https://pubmed.ncbi.nlm.nih.gov/36964137/