Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy
Markus Burkard, … , Bernd Wissinger, Peter Ruth
Markus Burkard, … , Bernd Wissinger, Peter Ruth
Published November 12, 2018
Citation Information: J Clin Invest. 2018;128(12):5663-5675. https://doi.org/10.1172/JCI96098.
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Research Article Genetics Ophthalmology

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

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.

Authors

Markus Burkard, Susanne Kohl, Timm Krätzig, Naoyuki Tanimoto, Christina Brennenstuhl, Anne E. Bausch, Katrin Junger, Peggy Reuter, Vithiyanjali Sothilingam, Susanne C. Beck, Gesine Huber, Xi-Qin Ding, Anja K. Mayer, Britta Baumann, Nicole Weisschuh, Ditta Zobor, Gesa-Astrid Hahn, Ulrich Kellner, Sascha Venturelli, Elvir Becirovic, Peter Charbel Issa, Robert K. Koenekoop, Günther Rudolph, John Heckenlively, Paul Sieving, Richard G. Weleber, Christian Hamel, Xiangang Zong, Martin Biel, Robert Lukowski, Matthias W. Seeliger, Stylianos Michalakis, Bernd Wissinger, Peter Ruth

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Figure 1

Pedigrees of patients and segregation of CNGB3 and CNGA3 disease alleles.

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Pedigrees of patients and segregation of CNGB3 and CNGA3 disease alleles...
Pedigrees are subdivided into 3 groups according to genotypes and correlated disease severity. Group 1: Compound heterozygosity for CNGB3/p.R403Q and a protein truncation mutation in CNGB3 and no mutation in CNGA3. Group 2: Homozygosity for the CNGB3/c.1208G>A;p.R403Q mutation and an additional heterozygous CNGA3 mutation. Group 3: Compound heterozygosity for CNGB3/c.1208G>A;p.R403Q and a protein truncation or splicing mutation in CNGB3 and an additional heterozygous CNGA3 mutation. The genotypes for CNGB3 and CNGA3 of all tested individuals are provided. The presence of 2 mutant CNGB3 alleles with homozygosity for the CNGB3/c.1208G>A;p.R403Q mutation was confirmed by qRT-PCR. Notably, siblings and parents carrying single heterozygous mutations in both CNGB3 and CNGA3 (CHRO208-I:2; CHRO251-I:1; CHRO979-III:1, and CHRO1050-I:1) are unaffected. The different mutations (M1-M3) in each family are defined above the respective pedigree. M1 was always selected for the p.R403Q mutation.