TY - JOUR
T1 - Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy
AU - Burkard, Markus
AU - Kohl, Susanne
AU - Krätzig, Timm
AU - Tanimoto, Naoyuki
AU - Brennenstuhl, Christina
AU - Bausch, Anne E.
AU - Junger, Katrin
AU - Reuter, Peggy
AU - Sothilingam, Vithiyanjali
AU - Beck, Susanne C.
AU - Huber, Gesine
AU - Ding, Xi Qin
AU - Mayer, Anja K.
AU - Baumann, Britta
AU - Weisschuh, Nicole
AU - Zobor, Ditta
AU - Hahn, Gesa Astrid
AU - Kellner, Ulrich
AU - Venturelli, Sascha
AU - Becirovic, Elvir
AU - Issa, Peter Charbel
AU - Koenekoop, Robert K.
AU - Rudolph, Günther
AU - Heckenlively, John
AU - Sieving, Paul
AU - Weleber, Richard G.
AU - Hamel, Christian
AU - Zong, Xiangang
AU - Biel, Martin
AU - Lukowski, Robert
AU - Seeliger, Matthias W.
AU - Michalakis, Stylianos
AU - Wissinger, Bernd
AU - Ruth, Peter
N1 - Funding Information:
We thank Sui Mei Chiu for patient referral, Kinga Bujakowska and Eric Pierce for supplying DNA of the probands published in ref. 26, Michel Michaelides for his willingness to discuss the case presented in ref. 27, and Fred Koch for his help in phenotypical mouse analysis. The study was supported by grants from the Deutsche Forschungsgemeinschaft (KFO134) to SK, BW, and PR, and BMBF grant 01GM1108A from the German Federal Ministry of Research and Education to SK and BW. M Burkard and SV were further supported by grants from the Institutional Strategy of the Eberhard Karls University of Tuebingen (Deutsche Forschungsgemeinschaft [DFG], ZUK 63), from the Wissenschaftsfoerderung der Deutschen Brauwirtschaft e.V. project B103, and the European Foundation for Alcohol Research (ERAB; ref. EA 15 28), and grants from Wissenschaftsfoerderung der Deutschen Brauwirtschaft e.V. project B103 and the European Foundation for Alcohol Research (ERAB; ref. EA 15 28). PCI was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Finally, we acknowledge support from Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of University of Tübingen. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Funding Information:
We thank Sui Mei Chiu for patient referral, Kinga Bujakowska and Eric Pierce for supplying DNA of the probands published in ref. 26, Michel Michaelides for his willingness to discuss the case presented in ref. 27, and Fred Koch for his help in phenotypical mouse analysis. The study was supported by grants from the Deutsche Forschungs-gemeinschaft (KFO134) to SK, BW, and PR, and BMBF grant 01GM1108A from the German Federal Ministry of Research and Education to SK and BW. M Burkard and SV were further supported by grants from the Institutional Strategy of the Eberhard Karls University of Tuebingen (Deutsche Forschungsgemeinschaft [DFG], ZUK 63), from the Wissenschaftsfoerderung der Deutschen Brau-wirtschaft e.V. project B103, and the European Foundation for Alcohol Research (ERAB; ref. EA 15 28), and grants from Wissenschafts-foerderung der Deutschen Brauwirtschaft e.V. project B103 and the European Foundation for Alcohol Research (ERAB; ref. EA 15 28). PCI was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Finally, we acknowledge support from Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of University of Tübingen. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Publisher Copyright:
Copyright 2018, American Society for Clinical Investigation.
PY - 2018/12/3
Y1 - 2018/12/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI96098
DO - 10.1172/JCI96098
M3 - Article
C2 - 30418171
AN - SCOPUS:85058291676
VL - 128
SP - 5663
EP - 5675
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -