Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy

• Published in: The Journal of clinical investigation 2018-12, Vol.128 (12), p.5663-5675
• Main Authors: 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, Charbel Issa, Peter, 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, Ruth, Peter
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Substitution; Animals; Biomedical research; Care and treatment; Color blindness; Color Vision Defects - genetics; Color Vision Defects - metabolism; Color Vision Defects - pathology; Congenital diseases; Cyclic Nucleotide-Gated Cation Channels - genetics; Cyclic Nucleotide-Gated Cation Channels - metabolism; Disease Models, Animal; Gene mutation; Genes; Genetic analysis; Genetic aspects; Genetic counseling; Genetic disorders; Genetic research; Genotype & phenotype; Genotypes; HEK293 Cells; Heredity; Heterozygote; Humans; Ion Channel Gating; Ligands; Medical genetics; Medical research; Mice; Mice, Transgenic; Mutation; Mutation, Missense; Optical tomography; Patients; Phenotypes; Photoreceptors; Questions and answers; Retina; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinal Diseases - pathology; Retinopathy; Rodents
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI96098

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.