{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T15:54:55Z","timestamp":1783785295633,"version":"3.55.0"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"ProRetina Foundation Germany","award":["ZIAEY000546"],"award-info":[{"award-number":["ZIAEY000546"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001116","name":"Foundation Fighting Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001116","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Usher syndrome (USH) is the most common form of hereditary deaf-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinae uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in M\u00fcller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones and outer segments (OS) of rods as well as at adhesive junctions between MGCs and photoreceptor cells (PRCs) in the outer limiting membrane (OLM). Our data provide evidence for the interaction of harmonin with OLM molecules in PRCs and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. We also demonstrate that primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our studies thus provide novel insights into PRC cell biology, USH1C pathophysiology and development of gene therapy treatment(s).<\/jats:p>","DOI":"10.1093\/hmg\/ddac211","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T11:25:21Z","timestamp":1661253921000},"page":"431-449","source":"Crossref","is-referenced-by-count":17,"title":["Expression and subcellular localization of\n                    <i>USH1C<\/i>\n                    \/harmonin in human retina provides insights into pathomechanisms and therapy"],"prefix":"10.1093","volume":"32","author":[{"given":"Kerstin","family":"Nagel-Wolfrum","sequence":"first","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"},{"name":"Johannes Gutenberg University Mainz Institute of Developmental Biology and Neurobiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin R","family":"Fadl","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"},{"name":"National Institutes of Health Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana M","family":"Becker","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten A","family":"Wunderlich","sequence":"additional","affiliation":[{"name":"Department of Physiological Genomics, BioMedical Center, Ludwig-Maximilian University Munich , 82152 Planegg-Martinsried , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Sturm","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"},{"name":"Johannes Gutenberg University Mainz Institute of Developmental Biology and Neurobiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Fritze","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burcu","family":"G\u00fcr","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4336-2768","authenticated-orcid":false,"given":"Lew","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Physiological Genomics, BioMedical Center, Ludwig-Maximilian University Munich , 82152 Planegg-Martinsried , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Andreani","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Computational Biology and Data Mining, Institute of Organismic & Molecular Evolution Biology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9754-9144","authenticated-orcid":false,"given":"Tobias","family":"Goldmann","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Brooks","sequence":"additional","affiliation":[{"name":"National Institutes of Health Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5274-2765","authenticated-orcid":false,"given":"Margaret R","family":"Starostik","sequence":"additional","affiliation":[{"name":"National Institutes of Health Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anagha","family":"Lokhande","sequence":"additional","affiliation":[{"name":"National Institutes of Health Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Apel","sequence":"additional","affiliation":[{"name":"University Medical Centre Mainz Department of Ophthalmology, , 55131 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6766-2530","authenticated-orcid":false,"given":"Karl R","family":"Fath","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"},{"name":"Department of Biology, Queens College of CUNY , Kissena Blvd, Flushing, NY 11367 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Stingl","sequence":"additional","affiliation":[{"name":"University of Tubingen University Eye Hospital, Centre for Ophthalmology, , 72076 Tubingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Kohl","sequence":"additional","affiliation":[{"name":"University of Tubingen Institute for Ophthalmic Research, Centre for Ophthalmology, , 72076 Tubingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M","family":"DeAngelis","sequence":"additional","affiliation":[{"name":"University of Buffalo Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, , NY 14209 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Schl\u00f6tzer-Schrehardt","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Department of Ophthalmology, , Erlangen-N\u00fcrnberg, 91054 Erlangen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana K","family":"Kim","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, Harvard Medical School Retina Service, , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah A","family":"Owen","sequence":"additional","affiliation":[{"name":"University of Utah Department of Ophthalmology and Visual Sciences, , Salt Lake City, UT 84132 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M","family":"Vetter","sequence":"additional","affiliation":[{"name":"University Medical Centre Mainz Department of Ophthalmology, , 55131 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"University Medical Centre Mainz Department of Ophthalmology, , 55131 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A","family":"Andrade-Navarro","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Computational Biology and Data Mining, Institute of Organismic & Molecular Evolution Biology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Grosche","sequence":"additional","affiliation":[{"name":"Department of Physiological Genomics, BioMedical Center, Ludwig-Maximilian University Munich , 82152 Planegg-Martinsried , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Swaroop","sequence":"additional","affiliation":[{"name":"National Institutes of Health Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4756-5872","authenticated-orcid":false,"given":"Uwe","family":"Wolfrum","sequence":"additional","affiliation":[{"name":"Johannes Gutenberg University Mainz Institute of Molecular Physiology, , 55128 Mainz , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"2023011922201597300_ref1","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/GIM.0b013e3181e5afb8","article-title":"Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children","volume":"12","author":"Kimberling","year":"2010","journal-title":"Genet. 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Eye Res."},{"key":"2023011922201597300_ref5","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a028274","article-title":"Photoreceptor cilia and retinal ciliopathies","volume":"9","author":"Bujakowska","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2023011922201597300_ref6","doi-asserted-by":"crossref","first-page":"6723","DOI":"10.3390\/ijms22136723","article-title":"Usher syndrome: genetics of a human ciliopathy","volume":"22","author":"Fuster-Garcia","year":"2021","journal-title":"Int. J. Mol. 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Mutat."},{"key":"2023011922201597300_ref10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/79171","article-title":"A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C","volume":"26","author":"Verpy","year":"2000","journal-title":"Nat. Genet."},{"key":"2023011922201597300_ref11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrn1517","article-title":"PDZ domain proteins of synapses","volume":"5","author":"Kim","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"2023011922201597300_ref12","doi-asserted-by":"crossref","first-page":"R262","DOI":"10.1093\/hmg\/ddl205","article-title":"Usher syndrome: molecular links of pathogenesis, proteins and pathways","volume":"15","author":"Kremer","year":"2006","journal-title":"Hum. Mol. 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