A Knockin Model with the Mouse Equivalent to the c.2299delG Mutation in Usherin Exhibits Early-Onset Hearing Loss and Progressive Retinal Degeneration.

Abstract

Usher syndrome (USH) is the predominant cause of inherited deaf-blindness, largely attributed to type 2A (USH2A) mutations, and particularly the prevalent c.2299delG mutation. While knockout models successfully replicated the cochlear phenotype of USH, recapitulating the retinal phenotype proved challenging. Given that patient mutations often lead to mutant protein expression rather than its absence, we developed a knockin model expressing the mouse equivalent of the c.2299delG mutation in USH2A. This model exhibited a functional decline in the retina, characterized by retinal degeneration, structural anomalies in the connecting cilium and outer segment, and mislocalization of mutant USH2A and its interacting partners ADGRV1 and whirlin. Remarkably, retinal symptoms manifested earlier than in the Ush2a^-/- mice. In the cochlea, the expression of truncated USH2A resulted in congenital hearing loss and disorganized stereocilia bundles. Thus, this knockin model underscores the necessity of expressing the mutant protein to faithfully reproduce the USH phenotype, providing valuable insights into the pathology of USH.