Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy
| Autor: | Richard G. Weleber, Robert Lukowski, M. W. Seeliger, Christina Brennenstuhl, Anne E. Bausch, Xiangang Zong, Sascha Venturelli, John R. Heckenlively, Vithiyanjali Sothilingam, Stylianos Michalakis, Susanne C. Beck, Günther Rudolph, Naoyuki Tanimoto, Ulrich Kellner, Peggy Reuter, Anja K. Mayer, Ditta Zobor, Susanne Kohl, Bernd Wissinger, Gesa Astrid Hahn, Britta Baumann, Paul A. Sieving, Xi-Qin Ding, Nicole Weisschuh, Christian P. Hamel, Martin Biel, Robert K. Koenekoop, Peter Ruth, Peter Charbel Issa, Timm Krätzig, Gesine Huber, Elvir Becirovic, Markus Burkard, Katrin Junger |
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| Přispěvatelé: | Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Achromatopsia [SDV]Life Sciences [q-bio] Mutant Color Vision Defects Eye medicine.disease_cause Medical and Health Sciences Transgenic Mice Cone dystrophy 2.1 Biological and endogenous factors Molecular genetics Aetiology Genetics Mutation General Medicine Phenotype Retinal Cone Photoreceptor Cells Ion Channel Gating Research Article Heterozygote medicine.medical_specialty Retinal Disorder Immunology Mutation Missense Cyclic Nucleotide-Gated Cation Channels Mice Transgenic Biology 03 medical and health sciences Retinal Diseases medicine Animals Humans Allele Retinopathy Eye Disease and Disorders of Vision Animal Neurosciences medicine.disease Brain Disorders Disease Models Animal Ophthalmology HEK293 Cells 030104 developmental biology Amino Acid Substitution Disease Models Missense |
| Zdroj: | The Journal of clinical investigation, vol 128, iss 12 Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (12), pp.5663--5675. ⟨10.1172/JCI96098⟩ |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci96098 |
| Popis: | International audience; Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide–gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3–/–) mice to obtain triallelic Cnga3+/– Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling. |
| Databáze: | OpenAIRE |
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