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Functional Consequences of a Rod Outer Segment Membrane Guanylate Cyclase (ROS-GC1) Gene Mutation Linked with Leber's Congenital Amaurosis

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The Unit of Regulatory and Molecular Biology, Departments of Cell Biology and Ophthalmology, NJMS, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084, and Institut fur Biologische Informationsverarbeitung, Forschungszentrum Julich, Postfach 1913, D-52425, Julich, Germany
Cite this: Biochemistry 1999, 38, 2, 509–515
Publication Date (Web):December 19, 1998
Copyright © 1999 American Chemical Society

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    ROS-GC1 is the original member of the subfamily of membrane guanylate cyclases with two Ca2+ switches, which have been defined as CRM1 and CRM2. These are separately located within the intracellular domain of the cyclase. CRM1 switches on the enzyme at nanomolar concentrations of Ca2+ and is linked with phototransduction; the other stimulates at micromolar Ca2+ concentrations and is predicted to be linked with retinal synaptic activity. Ca2+ acts indirectly via Ca2+-binding proteins, GCAP1 and CD-GCAP. GCAP1 is a modulator of the CRM1 switch, and CD-GCAP turns on the CRM2 switch. A Leber's congenital amaurosis, termed LCA1, involves F514S point mutation in ROS-GC1. The present study shows that the mutation severely damages its intrinsic cyclase activity and inactivates its CRM1 switch but does not affect the CRM2 switch. In addition, on the basis of the established modulatory features of ROS-GC1, it is predicted that, in two other forms of LCA1 involving deletion of nt 460C or 693C, there is a frameshift in ROS-GC1 gene, which results in the nonexpression of the cyclase. For the first time, the findings define the linkage of distinct molecular forms of LCA to ROS-GC1 in precise biochemical terms; they also explain the reasons for the insufficient production of cyclic GMP in photoreceptors to sustain phototransduction, which ultimately leads to the degeneration of the photoreceptors.

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     This study was supported by USHPS awards, EY 10828 (R.K.S.), NS 23744 (R.K.S.), and HL 58151 (T.D.), by the affiliated support of the Research to Prevent Blindness Inc., NY, by the Lions Eye Research Foundation, NJ, and by an award from the Deutsche Forschungsgemeinschaft (K.-W.K.).


    In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

     University of Medicine and Dentistry of New Jersey.


     Institut fur Biologische Informationsverarbeitung.

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    1. Patrick Zägel, Daniele Dell’Orco, and Karl-Wilhelm Koch . The Dimerization Domain in Outer Segment Guanylate Cyclase Is a Ca2+-Sensitive Control Switch Module. Biochemistry 2013, 52 (30) , 5065-5074.
    2. Igor V. Peshenko, Elena V. Olshevskaya, Suxia Yao, Hany H. Ezzeldin, Steven J. Pittler and Alexander M. Dizhoor . Activation of Retinal Guanylyl Cyclase RetGC1 by GCAP1: Stoichiometry of Binding and Effect of New LCA-Related Mutations. Biochemistry 2010, 49 (4) , 709-717.
    3. Amanda J. Scopelliti, Robyn V. Jamieson, Elizabeth H. Barnes, Benjamin Nash, Sulekha Rajagopalan, Elisa L. Cornish, John R. Grigg. A natural history study of autosomal dominant GUCY2D-associated cone–rod dystrophy. Documenta Ophthalmologica 2023, 147 (3) , 189-201.
    4. Teresa Duda, Rameshwar K. Sharma. Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder. Frontiers in Molecular Neuroscience 2023, 15
    5. Anne Rehkamp, Dirk Tänzler, Christian Tüting, Panagiotis L. Kastritis, Claudio Iacobucci, Christian H. Ihling, Marc Kipping, Karl-Wilhelm Koch, Andrea Sinz. First 3D-Structural Data of Full-Length Guanylyl Cyclase 1 in Rod-Outer-Segment Preparations of Bovine Retina by Cross-Linking/Mass Spectrometry. Journal of Molecular Biology 2021, 433 (10) , 166947.
    6. Yukito Takeda, Daiki Kubota, Noriko Oishi, Kaori Maruyama, Kiyoko Gocho, Kunihiko Yamaki, Tsutomu Igarashi, Hiroshi Takahashi, Shuhei Kameya. Novel GUCY2D Variant (E843Q) at Mutation Hotspot Associated with Macular Dystrophy in a Japanese Patient. Journal of Nippon Medical School 2020, 87 (2) , 92-99.
    7. Zaina Bouzia, Michalis Georgiou, Sarah Hull, Anthony G. Robson, Kaoru Fujinami, Tryfon Rotsos, Nikolas Pontikos, Gavin Arno, Andrew R. Webster, Alison J. Hardcastle, Alessia Fiorentino, Michel Michaelides. GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. American Journal of Ophthalmology 2020, 210 , 59-70.
    8. Teresa Duda, Alexandre Pertzev, Sarangan Ravichandran, Rameshwar K. Sharma. Ca2+-Sensor Neurocalcin δ and Hormone ANF Modulate ANF-RGC Activity by Diverse Pathways: Role of the Signaling Helix Domain. Frontiers in Molecular Neuroscience 2018, 11
    9. Teresa Duda, Alexander Pertzev, Rameshwar K. Sharma. CO2/bicarbonate modulates cone photoreceptor ROS-GC1 and restores its CORD6-linked catalytic activity. Molecular and Cellular Biochemistry 2018, 448 (1-2) , 91-105.
    10. Hanna Wimberg, Dorit Lev, Keren Yosovich, Prasanthi Namburi, Eyal Banin, Dror Sharon, Karl-Wilhelm Koch. Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis. Frontiers in Molecular Neuroscience 2018, 11
    11. Solomon S Merepa, Suzanne Broadgate, Sumathi Sekaran, Stephanie Halford. Genetics of the Retinal Dystrophies. 2018, 1-10.
    12. Dror Sharon, Hanna Wimberg, Yael Kinarty, Karl-Wilhelm Koch. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D. Progress in Retinal and Eye Research 2018, 63 , 69-91.
    13. S.R. Abbey, U. Eckhard, N. Solis, G. Marino, I. Matthew, C.M. Overall. The Human Odontoblast Cell Layer and Dental Pulp Proteomes and N-Terminomes. Journal of Dental Research 2018, 97 (3) , 338-346.
    14. Clint L. Makino, Teresa Duda, Alexandre Pertzev, Rameshwar K. Sharma. Experimental Approaches for Defining the Role of the Ca2+-Modulated ROS-GC System in Retinal Rods of Mouse. 2018, 129-158.
    15. Razek Georges Coussa, Irma Lopez Solache, Robert K. Koenekoop. Leber congenital amaurosis, from darkness to light: An ode to Irene Maumenee. Ophthalmic Genetics 2017, 38 (1) , 7-15.
    16. Rameshwar K. Sharma, Teresa Duda, Clint L. Makino. Integrative Signaling Networks of Membrane Guanylate Cyclases: Biochemistry and Physiology. Frontiers in Molecular Neuroscience 2016, 9
    17. Jeffrey Viviano, Anuradha Krishnan, Hao Wu, Venkat Venkataraman. Electrophoretic mobility shift in native gels indicates calcium-dependent structural changes of neuronal calcium sensor proteins. Analytical Biochemistry 2016, 494 , 93-100.
    18. Teresa Duda, Alexandre Pertzev, Clint L. Makino, Rameshwar K. Sharma. Bicarbonate and Ca2+ Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically. Frontiers in Molecular Neuroscience 2016, 9
    19. Karl-Wilhelm Koch, Daniele Dell’Orco. Protein and Signaling Networks in Vertebrate Photoreceptor Cells. Frontiers in Molecular Neuroscience 2015, 8
    20. Teresa Duda, Xiao-Hong Wen, Tomoki Isayama, Rameshwar K. Sharma, Clint L. Makino. Bicarbonate Modulates Photoreceptor Guanylate Cyclase (ROS-GC) Catalytic Activity. Journal of Biological Chemistry 2015, 290 (17) , 11052-11060.
    21. Rahel Zulliger, Muna I. Naash, Raju V.S. Rajala, Robert S. Molday, Seifollah Azadi. Impaired Association of Retinal Degeneration-3 with Guanylate Cyclase-1 and Guanylate Cyclase-activating Protein-1 Leads to Leber Congenital Amaurosis-1. Journal of Biological Chemistry 2015, 290 (6) , 3488-3499.
    22. Rameshwar K. Sharma, Teresa Duda. Membrane guanylate cyclase, a multimodal transduction machine: history, present, and future directions. Frontiers in Molecular Neuroscience 2014, 7
    23. Rameshwar K. Sharma, Clint L. Makino, David Hicks, Teresa Duda. ROS-GC interlocked Ca2+-sensor S100B protein signaling in cone photoreceptors: review. Frontiers in Molecular Neuroscience 2014, 7
    24. Ross F. Collery, Maria L. Cederlund, Breandán N. Kennedy. Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology. Experimental Eye Research 2013, 108 , 120-128.
    25. Daniel M. Lipinski, Miriam Thake, Robert E. MacLaren. Clinical applications of retinal gene therapy. Progress in Retinal and Eye Research 2013, 32 , 22-47.
    26. Petra Behnen, Daniele Dell'Orco, Karl-Wilhelm Koch. Involvement of the calcium sensor GCAP1 in hereditary cone dystrophies. Biological Chemistry 2010, 391 (6)
    27. Sukanya Karan, Jeanne M. Frederick, Wolfgang Baehr. Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion. Molecular and Cellular Biochemistry 2010, 334 (1-2) , 141-155.
    28. Karl-W. Koch, Teresa Duda, Rameshwar K. Sharma. Ca2+-modulated vision-linked ROS-GC guanylate cyclase transduction machinery. Molecular and Cellular Biochemistry 2010, 334 (1-2) , 105-115.
    29. David M. Hunt, Prateek Buch, Michel Michaelides. Guanylate cyclases and associated activator proteins in retinal disease. Molecular and Cellular Biochemistry 2010, 334 (1-2) , 157-168.
    30. Rameshwar K. Sharma, Teresa Duda. ROS-GC subfamily membrane guanylate cyclase-linked transduction systems: taste, pineal gland and hippocampus. Molecular and Cellular Biochemistry 2010, 334 (1-2) , 199-206.
    31. Rameshwar K. Sharma. Membrane guanylate cyclase is a beautiful signal transduction machine: overview. Molecular and Cellular Biochemistry 2010, 334 (1-2) , 3-36.
    32. Karl-Wilhelm Koch. Guanylate cyclase 2e. AfCS-Nature Molecule Pages 2009,
    33. Anneke I. den Hollander, Ronald Roepman, Robert K. Koenekoop, Frans P.M. Cremers. Leber congenital amaurosis: Genes, proteins and disease mechanisms. Progress in Retinal and Eye Research 2008, 27 (4) , 391-419.
    34. Andreas Helten, Werner Säftel, Karl‐Wilhelm Koch. Expression level and activity profile of membrane bound guanylate cyclase type 2 in rod outer segments. Journal of Neurochemistry 2007, 103 (4) , 1439-1446.
    35. R. K. Sharma. Molecular Neurobiology of Retinal Degeneration. 2007, 47-92.
    36. Robert K Koenekoop. An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology 2004, 49 (4) , 379-398.
    37. Satish R Tiyyagura, Shiva Kazerounian, Stephanie Schulz, Scott A Waldman, Giovanni M Pitari. Reciprocal Regulation and Integration of Signaling by Intracellular Calcium and Cyclic GMP. 2004, 69-94.
    38. Rando Allikmets. Leber congenital amaurosis: a genetic paradigm. Ophthalmic Genetics 2004, 25 (2) , 67-79.
    39. Ji‐Young Hwang, Christian Lange, Andreas Helten, Doris Höppner‐Heitmann, Teresa Duda, Rameshwar K. Sharma, Karl‐Wilhelm Koch. Regulatory modes of rod outer segment membrane guanylate cyclase differ in catalytic efficiency and Ca 2+ ‐sensitivity. European Journal of Biochemistry 2003, 270 (18) , 3814-3821.
    40. Nadine S. Dejneka, Enrico M. Surace, Jean Bennett. Gene Therapy for Leber Congenital Amaurosis. 2003, 415-422.
    41. Fernanda B. O. Porto, Isabelle Perrault, David Hicks, Jean-Michel Rozet, Noëlle Hanoteau, Sylvain Hanein, Josseline Kaplan, José A. Sahel. Prenatal Human Ocular Degeneration Occurs in Leber’s Congenital Amaurosis. 2003, 59-68.
    42. Karl-Wilhelm Koch. Target Recognition of Guanylate Cyclase By Guanylate Cyclase-Activating Proteins. 2002, 349-360.
    43. Richard J. Newbold, Evelyne C. Deery, Annette M. Payne, Susan E. Wilkie, David M. Hunt, Martin J. Warren. Guanylate Cyclase Activating Proteins, Guanylate Cyclase and Disease. 2002, 411-438.
    44. Rameshwar K. Sharma. Evolution of the membrane guanylate cyclase transduction system. 2002, 3-30.
    45. Teresa Duda, Karl-Wilhelm Koch. Retinal diseases linked with photoreceptor guanylate cyclase. 2002, 129-138.
    46. Elena V. Olshevskaya, Alexandre N. Ermilov, Alexander M. Dizhoor. Factors that affect regulation of cGMP synthesis in vertebrate photoreceptors and their genetic link to human retinal degeneration. 2002, 139-147.
    47. Karl-Wilhelm Koch, Teresa Duda, Rameshwar K Sharma. Photoreceptor specific guanylate cyclases in vertebrate phototransduction. 2002, 97-106.
    48. Venkateswar Venkataraman, Robert G. Nagele. Calcium-sensitive ROS-GC1 signaling outside of photoreceptors: A common theme. 2002, 117-124.
    49. BJ Wedel, DL Garbers. The Guanylyl Cyclase Family at Y2K. Annual Review of Physiology 2001, 63 (1) , 215-233.
    50. Ning Li, Izabela Sokal, J. Darin Bronson, Krzysztof Palczewski, Wolfgang Baehr. Identification of Functional Regions of Guanylate Cyclase-Activating Protein 1 (GCAP1) Using GCAP1/GCIP Chimeras. Biological Chemistry 2001, 382 (8)
    51. Christian Lange, Teresa Duda, Michael Beyermann, Rameshwar K. Sharma, Karl-Wilhelm Koch. Regions in vertebrate photoreceptor guanylyl cyclase ROS‐GC1 involved in Ca 2+ ‐dependent regulation by guanylyl cyclase‐activating protein GCAP‐1. FEBS Letters 1999, 460 (1) , 27-31.
    52. Robert K. Koenekoop. Leber Congenital Amaurosis. , 61-90.