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
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
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 -