WHRN

WHRN encodes whirlin, a multivalent PDZ-domain scaffold protein (two harmonin-N-like/harmonin-homology domains, three PDZ domains, a proline-rich region and a C-terminal PDZ-binding motif) that organizes macromolecular complexes in the sensory cells of the inner ear and retina. Distinct isoforms produced from alternative promoters carry out two spatially and temporally separable roles in cochlear hair cells. The long (full-length) isoform is a component of the transient ankle-link/USH2 complex at the base of developing stereocilia, where its N-terminal PDZ domains bind the cytoplasmic PDZ-binding motifs of the large transmembrane proteins usherin (USH2A) and ADGRV1 (VLGR1/GPR98) and heterodimerize with the paralogous scaffold PDZD7; multivalent interactions among these four proteins drive condensate-like assembly of the ankle-link complex, which maintains hair-bundle cohesion during morphogenesis. The short (C-terminal) isoform localizes to stereocilia tips, where together with the motor MYO15A and the actin regulator EPS8 it forms the tip complex that controls stereocilia elongation and staircase architecture. In retinal photoreceptors, whirlin scaffolds USH2A and ADGRV1 at the periciliary membrane complex adjacent to the connecting cilium, supporting periciliary organization and protein trafficking toward the outer segment, and it also interacts with MPP1/p55, CASK and CIB2. Whirlin self-associates, a property required for its phase-separation-mediated scaffolding. Biallelic loss of the long isoform causes Usher syndrome type 2D (deafness with retinitis pigmentosa), while variants disrupting the C-terminal region cause DFNB31 nonsyndromic sensorineural deafness. Whirlin has additionally been reported at hair-cell and photoreceptor synapses, in neuronal growth cones, and at axonal paranodes.

Disorders

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