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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
https://doi.org/10.1021/bi9824137
Copyright © 1999 American Chemical Society

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    Abstract

    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.).

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    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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