July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Digenic triallelic inheritance in cone photoreceptor cyclic nucleotide gated channel associated retinopathies
Author Affiliations & Notes
  • Susanne Kohl
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Markus Burkard
    Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
    Department of Vegetative and Clinical Physiology, University of Tuebingen, Tuebingen, Germany
  • Timm Kraetzig
    Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
  • Naoyuki Tanimoto
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Britta Baumann
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Martin Biel
    Center for Integrated Protein Science Munich CiPSM and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany
  • Robert Lukowski
    Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
  • Mathias W Seeliger
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Stylianos Michalakis
    Center for Integrated Protein Science Munich CiPSM and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Munich, Germany
  • Bernd Wissinger
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Peter Ruth
    Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
  • Footnotes
    Commercial Relationships   Susanne Kohl, None; Markus Burkard, None; Timm Kraetzig, None; Naoyuki Tanimoto, None; Britta Baumann, None; Martin Biel, None; Robert Lukowski, None; Mathias Seeliger, None; Stylianos Michalakis, None; Bernd Wissinger, None; Peter Ruth, None
  • Footnotes
    Support  Deutsche Forschungsgemeinschaft (DFG; KFO134, ZUK 63), German Federal Ministry of Research and Education (BMBF-01GM1108A), Institutional Strategy of the Eberhard Karls University of Tuebingen, Wissenschaftsfoerderung der Deutschen Brauwirtschaft e.V. (project B103), and the European Foundation for Alcohol Research (ERAB; ref. EA 15 28), National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC).
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 419. doi:
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    • Get Citation

      Susanne Kohl, Markus Burkard, Timm Kraetzig, Naoyuki Tanimoto, Britta Baumann, Martin Biel, Robert Lukowski, Mathias W Seeliger, Stylianos Michalakis, Bernd Wissinger, Peter Ruth; Digenic triallelic inheritance in cone photoreceptor cyclic nucleotide gated channel associated retinopathies. Invest. Ophthalmol. Vis. Sci. 2019;60(9):419.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in CNGA3 and CNGB3 together encode for the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel crucial for cone phototransduction, and are the most common cause of achromatopsia (ACHM). Patients carrying the CNGB3 mutation c.1208G>A;p.R403Q have been reported with a variable retinal phenotype ranging from complete and incomplete ACHM to moderate cone dysfunction or progressive cone and macular dystrophy.

Methods : Genetic screening of CNGA3 and CNGB3 in our cohort of >1000 ACHM patients, as well as literature research, was performed. In addition, patients with a clinical diagnosis of cone (n=316), cone-rod (n=450) and macular (n=408) dystrophy were specifically screened for CNGB3/R403Q. All patients carrying the CNGB3/R403Q mutation were sequenced for additional mutations in CNGA3. A Cngb3R403Q/R403Q mouse model was generated and crossbred with Cnga3-deficient mice (Cnga3-/-). Homozygous Cngb3R403Q/R403Q mice were evaluated and characterized for their retinal phenotype in comparison to triallelic digenic mice (Cngb3R403Q/R403Q;Cnga3+/-) and wildtype littermates.

Results : In our cohort, we identified 13 independent individuals who were homozygous for CNGB3/R403Q or (compound) heterozygous for CNGB3/R403Q and another pathogenic CNGB3 mutation, respectively, as well as 4 single heterozygous cases. Literature research provided evidence for 3 additional such cases. Genetic analysis revealed the co-occurrence of an additional heterozygous mutant CNGA3 allele in 62.5% (10/16) of the cases with biallelic CNGB3 mutations, thus most likely constituting a digenic triallelic cause of the disease phenotype. The analysis of digenic triallelic Cngb3R403Q/R403Q;Cnga3+/- mutant mice showed that - similar to human patients - the presence of one heterozygous Cnga3 null allele aggravates the cone dystrophy phenotype in homozygous Cngb3R403Q/R403Q mice.

Conclusions : Our investigations strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with ACHM and related diseases, linked to the CNGB3/R403Q mutation with important implications for diagnosis, prognosis and genetic counseling.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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