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TRPM1 Is Mutated in Patients with Autosomal-Recessive Complete Congenital Stationary Night Blindness |
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| Authors: | Isabelle Audo,Susanne Kohl,Francis L. Munier,Xavier Guillonneau,Saddek Mohand-Saï d,Kinga Bujakowska,Emeline F. Nandrot,Birgit Lorenz,Ulrich Kellner,Antje Bernd,Veselina Moskova-Doumanova,Marie-Elise Lancelot,Charlotte M. Poloschek,Sabine Defoort-Dhellemmes,Thierry Lé veillard,Christian P. Hamel,Elfride De Baere,Samuel G. Jacobson,José -Alain Sahel,Shomi S. Bhattacharya,Christina Zeitz |
| Affiliation: | 1 INSERM, UMR_S968, F-75012, Paris, France 2 CNRS, UMR_7210, F-75012, Paris, France 3 UPMC Univ. Paris 06, UMR_S968, Institut de la Vision, 17, Rue Moreau, F-75012, Paris, France 4 CMR/CIC 503 INSERM, CHNO des Quinze-Vingts, F-75012, Paris, France 5 Department of Molecular Genetics, Institute of Ophthalmology, EC1V 9EL London, UK 6 Molecular Genetics Laboratory, Institute for Ophthalmic Research, 72076 Tuebingen, Germany 7 Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium 8 Department of Ophthalmology, Ghent University, 9000 Ghent, Belgium 9 Unit of Oculogenetics, Jules Gonin Eye Hospital, 1004 Lausanne, Switzerland 10 Department of Ophthalmology, Justus-Liebig-University Giessen, Universitaetsklinikum Giessen and Marburg GmbH Giessen Campus, 35392 Giessen, Germany 11 Augen Zentrum Siegburg, 53721 Siegburg, Germany 12 Department of Ophthalmology, University Medical Center Regensburg, 93042 Regensburg, Germany 13 University Eye Clinic Centre for Ophthalmology University Clinics Tuebingen, 72076 Tuebingen, Germany 14 Department of Ophthalmology, University of Freiburg, 79106 Freiburg, Germany 15 Laboratoire Neurosciences Fonctionnelles et Pathologies, CNRS FRE 2726, Hôpital Roger Salengro, 59037 Lille, France 16 Inserm U. 583, Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, 34091 Montpellier, France 17 Institut de Recherche en Ophtalmologie (IRO), Ecole Polytechnique Fédérale de Lausanne, University of Lausanne, 1950 Sion, Switzerland 18 Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, 8603 Schwerzenbach, Switzerland 19 University of Pennsylvania, Scheie Eye Institute, Philadelphia, PA 19104, USA |
| Abstract: | Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in ∼60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells. |
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