%0 Journal Article
%T Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel每associated retinopathy
%A Anja K. Mayer
%A Anne E. Bausch
%A Bernd Wissinger
%A Britta Baumann
%A Christian Hamel
%A Christina Brennenstuhl
%A Ditta Zobor
%A Elvir Becirovic
%A Gesa-Astrid Hahn
%A Gesine Huber
%A G邦nther Rudolph
%A John Heckenlively
%A Katrin Junger
%A Markus Burkard
%A Martin Biel
%A Matthias W. Seeliger
%A Naoyuki Tanimoto
%A Nicole Weisschuh
%A Paul Sieving
%A Peggy Reuter
%A Peter Charbel Issa
%A Peter Ruth
%A Richard G. Weleber
%A Robert K. Koenekoop
%A Robert Lukowski
%A Sascha Venturelli
%A Stylianos Michalakis
%A Susanne C. Beck
%A Susanne Kohl
%A Timm Krˋtzig
%A Ulrich Kellner
%A Vithiyanjali Sothilingam
%A Xi-Qin Ding
%A Xiangang Zong
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI96098
%X Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide每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每/每) mice to obtain triallelic Cnga3+/每 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
%U https://www.jci.org/articles/view/96098