Expression and subcellular localization of USH1C /harmonin in human retina provides insights into pathomechanisms and therapy
Year: 2022
Type: article
Abstract: 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 Müller 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).
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddac211
Authors: Kerstin Nagel-Wolfrum, Benjamin R Fadl, Mirjana M Becker, Kirsten A Wunderlich, Jessica Schäfer, Daniel Sturm, Jacques Fritze, Burcu Gür, Lew Kaplan, Tommaso Andreani, Tobias Goldmann, Matthew Brooks, Margaret R Starostik, Anagha Lokhande, Melissa Apel, Karl R Fath, Katarina Stingl, Susanne Kohl, Margaret M DeAngelis, Ursula Schlötzer-Schrehardt, Ivana K Kim, Leah A Owen, Jan M Vetter, Norbert Pfeiffer, Miguel A Andrade-Navarro, Antje Grosche, Anand Swaroop, Uwe Wolfrum
Institutions: Johannes Gutenberg University Mainz, National Institutes of Health, National Eye Institute, Ludwig-Maximilians-Universität München, University Medical Center of the Johannes Gutenberg University Mainz, Queens College, CUNY, Universitätsklinikum Tübingen, University of Tübingen, University at Buffalo, State University of New York, Friedrich-Alexander-Universität Erlangen-Nürnberg, Massachusetts Eye and Ear Infirmary, Harvard University, University of Utah
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,206
Awards: G1796319831, G3333578955, Systems-Biology Analysis of Mechanisms Informing Preeclampsia-Mediated ROP Protection, A systems biology approach to dissect cilia function and its disruption in human genetic disease, G611703824, G7486814348, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher), Mechanisms, modeling and therapies of retinal and macular neurodegeneration
OpenAlex ID: W4292749613