{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWhirlin, encoded by the WHRN (DFNB31) gene, is a multi‐domain PDZ scaffold protein that plays a pivotal role in the inner ear by organizing submembranous protein complexes essential for actin polymerization and membrane growth. In sensory hair cells of the organ of Corti, whirlin is crucial for the elongation and maintenance of the stereocilia—specialized actin‐rich protrusions required for mechanotransduction. Studies in the whirler mouse mutant and analyses of the whirlin–myosin 15–Eps8 complex (demonstrating liquid–liquid phase separation that promotes actin bundling) provide strong evidence for its central function in assembling and stabilizing the molecular machinery necessary for proper auditory function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in the auditory system, whirlin is a central organizer in the protein networks whose disruption leads to Usher syndrome type II. Here, whirlin interacts with key partners—including USH2A, VLGR1, SANS, and espin—to form multiprotein complexes situated at both the synaptic regions of hair cells and the periciliary region of retinal photoreceptors. These interactions are critical for maintaining synaptic adhesion, signaling, and overall cellular architecture in these sensory cells. Notably, mutations affecting the long isoform of whirlin can result in the combined auditory and visual impairments of Usher syndrome, whereas alterations confined to the C-terminal portion are typically linked to non‐syndromic hearing loss."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, alternative splicing of the WHRN gene gives rise to distinct isoforms that underlie its pleiotropic functions in various tissues. Differential expression of these isoforms can explain why some mutations lead solely to auditory deficits while others contribute to the broader phenotype of Usher syndrome with retinal degeneration. In-depth structural studies of whirlin’s tandem PDZ domains have revealed complex folding dynamics—including the formation of functional misfolded intermediates—that are likely critical for its scaffolding capabilities. Emerging evidence also suggests that aberrant expression of particular whirlin isoforms may be implicated in non‐sensory diseases (for example, in colorectal cancer), highlighting the protein’s diverse roles in cellular organization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chan Choo Yap, Fengyi Liang, Yasuhiro Yamazaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CIP98, a novel PDZ domain protein, is expressed in the central nervous system and interacts with calmodulin-dependent serine kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1471-4159.2003.01647.x"}], "href": "https://doi.org/10.1046/j.1471-4159.2003.01647.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12641734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12641734"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Philomena Mburu, Mirna Mustapha, Anabel Varela, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1208"}], "href": "https://doi.org/10.1038/ng1208"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12833159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12833159"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Erwin van Wijk, Bert van der Zwaag, Theo Peters, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddi490"}], "href": "https://doi.org/10.1093/hmg/ddi490"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16434480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16434480"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Zubair M Ahmed, Gregory I Frolenkov, Saima Riazuddin "}, {"type": "b", "children": [{"type": "t", "text": "Usher proteins in inner ear structure and function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Physiol Genomics (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/physiolgenomics.00135.2013"}], "href": "https://doi.org/10.1152/physiolgenomics.00135.2013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24022220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24022220"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lin Lin, Yingdong Shi, Mengli Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2021.108770"}], "href": "https://doi.org/10.1016/j.celrep.2021.108770"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33626355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33626355"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Inga Ebermann, Hendrik P N Scholl, Peter Charbel Issa, et al. 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