title: Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1.
abstract: One-fifth of all cases of Leber congenital amaurosis are type 1 (LCA1). LCA1 is a severe form of retinal dystrophy caused by loss-of-function mutations in guanylate cyclase 1 (GC1), a key member of the phototransduction cascade involved in modulating the photocurrents. Although GC1 has been studied for some time, the mechanisms responsible for its regulation and membrane targeting are not fully understood. We reported earlier that retinal degeneration 3 (RD3) protein interacts with GC1 and promotes its targeting to the photoreceptor outer segments (POS). Here, we extend our studies to show a direct association between RD3 and guanylate cyclase activating protein 1 (GCAP1). Furthermore, we demonstrate that this functional interaction is important for GC1 targeting to POS. We also show that most LCA1-causing mutations in GC1 result in lost GC1 interaction with RD3 or GC1 being targeted to the plasma membrane. Our data suggest that GC1, GCAP1, and RD3 form a complex in the endoplasmic reticulum that targets GC1 to POS. Interruption of this assembly is likely the underlying mechanism for a subset of LCA1. This study offers insights for the development of therapeutic strategies to treat this severe form of blindness.
authors.affiliation: From the Departments of Cell Biology.
authors.forename: Rahel
authors.initials: R
authors.lastname: Zulliger
authors.affiliation: From the Departments of Cell Biology.
authors.forename: Muna I
authors.initials: MI
authors.lastname: Naash
authors.affiliation: From the Departments of Cell Biology, Ophthalmology, and Physiology, University of Oklahoma Health Sciences Center and the Dean McGee Eye Institute, Oklahoma City, Oklahoma 73104 and.
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Molday
authors.affiliation: From the Departments of Cell Biology, the Dean McGee Eye Institute, Oklahoma City, Oklahoma 73104 and sazadi@ouhsc.edu.
authors.forename: Seifollah
authors.initials: S
authors.lastname: Azadi
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D051604:Guanylate Cyclase-Activating Proteins; C496737:Guca1a protein, mouse; D009687:Nuclear Proteins; C477438:RD3 protein, human; D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; C516799:retinal degeneration 3 protein, mouse; D006162:Guanylate Cyclase
keywords: Guanylate Cyclase (Guanylyl Cyclase); Photoreceptor; Protein Targeting; Retinal Degeneration; Trafficking