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Title: Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment

Abstract

Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis ofmore » in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients.« less

Authors:
 [1];  [2];  [2];  [3];  [3];  [2];  [2];  [4];  [2];  [3];  [2];  [1];  [2];
+ Show Author Affiliations
  1. Temple Univ., Philadelphia, PA (United States). Dept. of Biology, College of Science and Technology
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Clinical Studies-Philadelphia, School of Veterinary Medicine
  3. Temple Univ., Philadelphia, PA (United States). Inst. for Computational Molecular Science
  4. Veterinary Vision (United Kingdom)
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1565391
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 9; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics

Citation Formats

Tanaka, Naoto, Dutrow, Emily V., Miyadera, Keiko, Delemotte, Lucie, MacDermaid, Christopher M., Reinstein, Shelby L., Crumley, William R., Dixon, Christopher J., Casal, Margret L., Klein, Michael L., Aguirre, Gustavo D., Tanaka, Jacqueline C., Guziewicz, Karina E., and Khanna, Hemant. Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment. United States: N. p., 2015. Web. doi:10.1371/journal.pone.0138943.
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Tanaka, Naoto, Dutrow, Emily V., Miyadera, Keiko, Delemotte, Lucie, MacDermaid, Christopher M., Reinstein, Shelby L., Crumley, William R., Dixon, Christopher J., Casal, Margret L., Klein, Michael L., Aguirre, Gustavo D., Tanaka, Jacqueline C., Guziewicz, Karina E., & Khanna, Hemant. Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment. United States. https://doi.org/10.1371/journal.pone.0138943
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Tanaka, Naoto, Dutrow, Emily V., Miyadera, Keiko, Delemotte, Lucie, MacDermaid, Christopher M., Reinstein, Shelby L., Crumley, William R., Dixon, Christopher J., Casal, Margret L., Klein, Michael L., Aguirre, Gustavo D., Tanaka, Jacqueline C., Guziewicz, Karina E., and Khanna, Hemant. Fri . "Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment". United States. https://doi.org/10.1371/journal.pone.0138943. https://www.osti.gov/servlets/purl/1565391.
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@article{osti_1565391,
title = {Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment},
author = {Tanaka, Naoto and Dutrow, Emily V. and Miyadera, Keiko and Delemotte, Lucie and MacDermaid, Christopher M. and Reinstein, Shelby L. and Crumley, William R. and Dixon, Christopher J. and Casal, Margret L. and Klein, Michael L. and Aguirre, Gustavo D. and Tanaka, Jacqueline C. and Guziewicz, Karina E. and Khanna, Hemant},
abstractNote = {Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients.},
doi = {10.1371/journal.pone.0138943},
journal = {PLoS ONE},
number = 9,
volume = 10,
place = {United States},
year = {Fri Sep 25 00:00:00 EDT 2015},
month = {Fri Sep 25 00:00:00 EDT 2015}
}
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Structure of the carboxy-terminal region of a KCNH channel
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Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels
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Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1
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Restoration of cone vision in a mouse model of achromatopsia
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Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa
journal, January 2012

  • Beltran, W. A.; Cideciyan, A. V.; Lewin, A. S.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 6
  • DOI: 10.1073/pnas.1118847109

Structural Basis for the cAMP-dependent Gating in the Human HCN4 Channel
journal, September 2010

  • Xu, Xinping; Vysotskaya, Zhanna V.; Liu, Qinglian
  • Journal of Biological Chemistry, Vol. 285, Issue 47
  • DOI: 10.1074/jbc.m110.152033

Interactions between S4-S5 Linker and S6 Transmembrane Domain Modulate Gating of HERG K + Channels
journal, February 2002

  • Tristani-Firouzi, Martin; Chen, Jun; Sanguinetti, Michael C.
  • Journal of Biological Chemistry, Vol. 277, Issue 21
  • DOI: 10.1074/jbc.m200410200

Coupling between Voltage Sensors and Activation Gate in Voltage-gated K + Channels
journal, October 2002

  • Lu, Zhe; Klem, Angela M.; Ramu, Yajamana
  • The Journal of General Physiology, Vol. 120, Issue 5
  • DOI: 10.1085/jgp.20028696

Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial
journal, October 2008

  • Hauswirth, William W.; Aleman, Tomas S.; Kaushal, Shalesh
  • Human Gene Therapy, Vol. 19, Issue 10
  • DOI: 10.1089/hum.2008.107

Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year
journal, September 2009

  • Cideciyan, Artur V.; Hauswirth, William W.; Aleman, Tomas S.
  • Human Gene Therapy, Vol. 20, Issue 9
  • DOI: 10.1089/hum.2009.086

Clustal W and Clustal X version 2.0
journal, September 2007

Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3
journal, August 2002

Gene therapy rescues cone function in congenital achromatopsia
journal, April 2010

  • Komáromy, András M.; Alexander, John J.; Rowlan, Jessica S.
  • Human Molecular Genetics, Vol. 19, Issue 13
  • DOI: 10.1093/hmg/ddq136

Achromatopsia in three sibling Labrador Retrievers in the UK
journal, March 2015

  • Dixon, Christopher J.
  • Veterinary Ophthalmology, Vol. 19, Issue 1
  • DOI: 10.1111/vop.12265

Regulation of Human Cone Cyclic Nucleotide-Gated Channels by Endogenous Phospholipids and Exogenously Applied Phosphatidylinositol 3,4,5-trisphosphate
journal, October 2006

  • Bright, Scott R.; Rich, Elizabeth D.; Varnum, Michael D.
  • Molecular Pharmacology, Vol. 71, Issue 1
  • DOI: 10.1124/mol.106.026401

Protein Design: A Hierarchic Approach
journal, November 1995

Theoretical and Computational Protein Design
journal, May 2011

CNGA3 achromatopsia-associated mutation potentiates the phosphoinositide sensitivity of cone photoreceptor CNG channels by altering intersubunit interactions
journal, July 2013

  • Dai, Gucan; Varnum, Michael D.
  • American Journal of Physiology-Cell Physiology, Vol. 305, Issue 2
  • DOI: 10.1152/ajpcell.00037.2013

Impaired Opsin Targeting and Cone Photoreceptor Migration in the Retina of Mice Lacking the Cyclic Nucleotide-Gated Channel CNGA3
journal, April 2005

  • Michalakis, Stylianos; Geiger, Heidi; Haverkamp, Silke
  • Investigative Opthalmology & Visual Science, Vol. 46, Issue 4
  • DOI: 10.1167/iovs.04-1503

Transmembrane S1 Mutations in CNGA3 from Achromatopsia 2 Patients Cause Loss of Function and Impaired Cellular Trafficking of the Cone CNG Channel
journal, July 2005

  • Patel, Kirti A.; Bartoli, Kristen M.; Fandino, Richard A.
  • Investigative Opthalmology & Visual Science, Vol. 46, Issue 7
  • DOI: 10.1167/iovs.05-0179

A Naturally Occurring Mouse Model of Achromatopsia: Characterization of the Mutation in Cone Transducin and Subsequent Retinal Phenotype
journal, May 2013

  • Jobling, Andrew I.; Vessey, Kirstan A.; Waugh, Michelle
  • Investigative Opthalmology & Visual Science, Vol. 54, Issue 5
  • DOI: 10.1167/iovs.13-11831

A Novel Form of Progressive Retinal Atrophy in Swedish Vallhund Dogs
journal, September 2014

Mechanism of Electromechanical Coupling in Voltage-Gated Potassium Channels
journal, January 2012

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    Works referencing / citing this record:

    Gene therapy for achromatopsia
    journal, March 2017

    • Michalakis, Stylianos; Schön, Christian; Becirovic, Elvir
    • The Journal of Gene Medicine, Vol. 19, Issue 3
    • DOI: 10.1002/jgm.2944

    Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options
    journal, January 2018

    Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy
    journal, March 2018

    • Michalakis, Stylianos; Becirovic, Elvir; Biel, Martin
    • International Journal of Molecular Sciences, Vol. 19, Issue 3, p. 749
    • DOI: 10.3390/ijms19030749

    Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep
    journal, March 2017

    • Gootwine, Elisha; Abu-Siam, Mazen; Obolensky, Alexey
    • Investigative Opthalmology & Visual Science, Vol. 58, Issue 3
    • DOI: 10.1167/iovs.16-20986

    Concepts and Strategies in Retinal Gene Therapy
    journal, October 2017

    • Aguirre, Gustavo D.
    • Investigative Opthalmology & Visual Science, Vol. 58, Issue 12
    • DOI: 10.1167/iovs.17-22978
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