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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5663-5675 |
| Number of pages | 13 |
| Journal | Journal of Clinical Investigation |
| Volume | 128 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 3 2018 |
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ASJC Scopus subject areas
- Medicine(all)
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Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy. / 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; Issa, Peter Charbel; Koenekoop, Robert K.; Rudolph, Günther; Heckenlively, John; Sieving, Paul; Weleber, Richard; Hamel, Christian; Zong, Xiangang; Biel, Martin; Lukowski, Robert; Seeliger, Matthias W.; Michalakis, Stylianos; Wissinger, Bernd; Ruth, Peter.
In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5663-5675.Research output: Contribution to journal › Article
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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.
UR - http://www.scopus.com/inward/record.url?scp=85058291676&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058291676&partnerID=8YFLogxK
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 -