{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSH1C encodes harmonin, a multi‐PDZ domain scaffold protein central to the organization and stabilization of protein complexes that underlie mechanotransduction in sensory hair cells. Harmonin binds directly to key components of the hair‐bundle apparatus—most notably cadherin 23—and bundles F‐actin to anchor these transmembrane proteins to the cytoskeleton. In this manner, harmonin participates in a functional unit with myosin VIIa and cadherin 23 that is essential for the cohesion and proper architecture of the stereocilia as well as for the formation of tip‐link complexes in brush border microvilli. Such interactions and assemblies have been further shown to rely on novel binding modes and even liquid–liquid phase separation, suggesting that dynamic condensation of the USH1 protein complex is important for transducing mechanical forces."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its structural role in hair cells, extensive alternative splicing of USH1C gives rise to multiple harmonin isoforms that exhibit tissue‐specific expression. Mutations in USH1C have been identified in patients with Usher syndrome type 1 as well as in cases of nonsyndromic recessive deafness, underscoring the essential role of harmonin in auditory function. Mutation screening across diverse populations has revealed a broad allelic heterogeneity—including splice‐site alterations, small insertions/deletions, and missense variants—that often result in unstable transcripts or aberrant protein conformations. Moreover, studies have indicated that harmonin may be differentially regulated in other tissues; for example, changes in placental gene expression and the presence of harmonin autoantibodies have been documented, hinting at additional roles beyond the inner ear."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent investigations in human retinal tissue have further expanded our understanding of harmonin’s function. In the retina, harmonin is not only expressed in photoreceptors but also in Müller glia cells, where it localizes to structures such as the outer limiting membrane and the apical microvilli. Structural studies reveal that harmonin can switch between open and closed conformations through intramolecular interactions—features that may fine‑tune its binding affinities with partners like cadherin 23. These mechanistic insights underlie emerging therapeutic strategies, including gene augmentation and targeted repair approaches, aimed at restoring harmonin function to mitigate retinal degeneration in Usher syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Batiste Boëda, Aziz El-Amraoui, Amel Bahloul, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-004-1227-2"}], "href": "https://doi.org/10.1007/s00439-004-1227-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15660226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15660226"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Inga Ebermann, Irma Lopez, Maria Bitner-Glindzicz, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the USH1C gene associated with sector retinitis pigmentosa and hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Retina (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/IAE.0b013e31820d3fd1"}], "href": "https://doi.org/10.1097/IAE.0b013e31820d3fd1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21487335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21487335"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Samer Khateb, Lina Zelinger, Tamar Ben-Yosef, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequencing identifies a founder frameshift mutation in an alternative exon of USH1C as the cause of autosomal recessive retinitis pigmentosa with late-onset hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0051566"}], "href": "https://doi.org/10.1371/journal.pone.0051566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23251578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23251578"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Bharti Katbamna, Nicole Klutz, Charles Pudrith, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prenatal smoke exposure: effects on infant auditory system and placental gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurotoxicol Teratol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ntt.2013.04.008"}], "href": "https://doi.org/10.1016/j.ntt.2013.04.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23665419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23665419"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Vito Lampasona, Laura Passerini, Federica Barzaghi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0078664"}], "href": "https://doi.org/10.1371/journal.pone.0078664"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24250806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24250806"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Aparna Ganapathy, Nishtha Pandey, C R Srikumari Srisailapathy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0084773"}], "href": "https://doi.org/10.1371/journal.pone.0084773"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24416283"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24416283"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Muhammad Noman, Shazia A Bukhari, Sakina Rehman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-020-06016-y"}], "href": "https://doi.org/10.1007/s11033-020-06016-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33231815"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33231815"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Nora Overlack, Tobias Goldmann, Uwe Wolfrum, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.12-9812"}], "href": "https://doi.org/10.1167/iovs.12-9812"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22661463"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22661463"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Jianchao Li, Yunyun He, Meredith L Weck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1702251114"}], "href": "https://doi.org/10.1073/pnas.1702251114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28439001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28439001"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Kerstin Nagel-Wolfrum, Benjamin R Fadl, Mirjana M Becker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and subcellular localization of USH1C/harmonin in human retina provides insights into pathomechanisms and therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddac211"}], "href": "https://doi.org/10.1093/hmg/ddac211"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35997788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35997788"}]}]}]}