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

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 BecirovicPeter Charbel Issa, Robert K. Koenekoop, Günther Rudolph, John Heckenlively, Paul Sieving, Richard Weleber, Christian Hamel, Xiangang Zong, Martin Biel, Robert Lukowski, Matthias W. Seeliger, Stylianos Michalakis, Bernd Wissinger, Peter Ruth

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)5663-5675
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

Fingerprint

Retinal Cone Photoreceptor Cells
Color Vision Defects
Mutation
Phenotype
Alleles
Inheritance Patterns
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Genetic Counseling
Genetic Association Studies
Ion Channels
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Burkard, M., Kohl, S., Krätzig, T., Tanimoto, N., Brennenstuhl, C., Bausch, A. E., ... Ruth, P. (2018). Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy. Journal of Clinical Investigation, 128(12), 5663-5675. https://doi.org/10.1172/JCI96098

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 journalArticle

Burkard, M, Kohl, S, Krätzig, T, Tanimoto, N, Brennenstuhl, C, Bausch, AE, Junger, K, Reuter, P, Sothilingam, V, Beck, SC, Huber, G, Ding, XQ, Mayer, AK, Baumann, B, Weisschuh, N, Zobor, D, Hahn, GA, Kellner, U, Venturelli, S, Becirovic, E, Issa, PC, Koenekoop, RK, Rudolph, G, Heckenlively, J, Sieving, P, Weleber, R, Hamel, C, Zong, X, Biel, M, Lukowski, R, Seeliger, MW, Michalakis, S, Wissinger, B & Ruth, P 2018, 'Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5663-5675. https://doi.org/10.1172/JCI96098
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. / Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5663-5675.
@article{f6a27ce28d954bd399947a306b6c192c,
title = "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.",
author = "Markus Burkard and Susanne Kohl and Timm Kr{\"a}tzig and Naoyuki Tanimoto and Christina Brennenstuhl and Bausch, {Anne E.} and Katrin Junger and Peggy Reuter and Vithiyanjali Sothilingam and Beck, {Susanne C.} and Gesine Huber and Ding, {Xi Qin} and Mayer, {Anja K.} and Britta Baumann and Nicole Weisschuh and Ditta Zobor and Hahn, {Gesa Astrid} and Ulrich Kellner and Sascha Venturelli and Elvir Becirovic and Issa, {Peter Charbel} and Koenekoop, {Robert K.} and G{\"u}nther Rudolph and John Heckenlively and Paul Sieving and Richard Weleber and Christian Hamel and Xiangang Zong and Martin Biel and Robert Lukowski and Seeliger, {Matthias W.} and Stylianos Michalakis and Bernd Wissinger and Peter Ruth",
year = "2018",
month = "12",
day = "3",
doi = "10.1172/JCI96098",
language = "English (US)",
volume = "128",
pages = "5663--5675",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",

}

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 -