USH2A

USH2A encodes usherin, one of the largest proteins in the human proteome (~5202 aa in its long isoform b), expressed principally in cochlear hair cells and retinal photoreceptors. The long isoform is a single-pass type I transmembrane protein whose enormous ectodomain — laminin N-terminal, laminin EGF-like and laminin G-like domains plus ~35 fibronectin type III repeats — forms extracellular adhesion fibers, while its short cytoplasmic tail ends in a class-I PDZ-binding motif (DTHL) that binds the PDZ scaffolds whirlin (WHRN) and PDZD7. In developing cochlear hair cells, usherin and the adhesion GPCR ADGRV1, organized by WHRN and PDZD7, assemble the ankle-link complex (USH2 complex), whose extracellular portions form the transient ankle links that interconnect stereocilia at their bases during hair-bundle development (in mouse roughly P2-P12, disappearing as cochlear bundles mature); this complex, whose condensation is driven by multivalent PDZ-mediated interactions and liquid-liquid phase separation, is required for normal stereocilia organization and hearing. In photoreceptors the same complex localizes to the periciliary membrane compartment of the apical inner segment surrounding the connecting cilium, where it supports periciliary architecture and photoreceptor cell maintenance. A shorter secreted isoform (isoform A) and the shared N-terminal region associate with basement membranes of many epithelia and of Bruch's membrane in the eye, where the laminin EGF-like domains bind the 7S domain of collagen IV. Biallelic loss-of-function variants in USH2A cause Usher syndrome type 2A (congenital moderate-to-severe hearing loss with progressive retinitis pigmentosa) and nonsyndromic retinitis pigmentosa (RP39), making USH2A the most frequently mutated Usher syndrome gene.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.