1. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy
- Author
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Burkard, Markus, Kohl, Susanne, Krätzig, Timm, Tanimoto, Naoyuki, Brennenstuhl, Christina, Bausch, Anne E, Junger, Katrin, Reuter, Peggy, Sothilingam, Vithiyanjali, Beck, Susanne C, Huber, Gesine, Ding, Xi-Qin, Mayer, Anja K, Baumann, Britta, Weisschuh, Nicole, Zobor, Ditta, Hahn, Gesa-Astrid, Kellner, Ulrich, Venturelli, Sascha, Becirovic, Elvir, Issa, Peter Charbel, Koenekoop, Robert K, Rudolph, Günther, Heckenlively, John, Sieving, Paul, Weleber, Richard G, Hamel, Christian, Zong, Xiangang, Biel, Martin, Lukowski, Robert, Seeliger, Matthias W, Michalakis, Stylianos, Wissinger, Bernd, and Ruth, Peter
- Subjects
Genetics ,Neurosciences ,Brain Disorders ,Eye Disease and Disorders of Vision ,Aetiology ,2.1 Biological and endogenous factors ,Eye ,Amino Acid Substitution ,Animals ,Color Vision Defects ,Cyclic Nucleotide-Gated Cation Channels ,Disease Models ,Animal ,HEK293 Cells ,Heterozygote ,Humans ,Ion Channel Gating ,Mice ,Mice ,Transgenic ,Mutation ,Mutation ,Missense ,Retinal Cone Photoreceptor Cells ,Retinal Diseases ,Molecular genetics ,Ophthalmology ,Retinopathy ,Medical and Health Sciences ,Immunology - Abstract
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.
- Published
- 2018