title: Mistrafficking of prenylated proteins causes retinitis pigmentosa 2.
abstract: The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Δ (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The Rp2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. Rp2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the Rp2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA houbin.zhang@gmail.com wbaehr@hsc.utah.edu.
authors.forename: Houbin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Christin
authors.initials: C
authors.lastname: Hanke-Gogokhia
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Cecilia D
authors.initials: CD
authors.lastname: Gerstner
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: *The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA; Department of Biochemistry and Biology, University of Potsdam, Potsdam-Golm, Germany; and Department of Biology, University of Utah, Salt Lake City, Utah, USA houbin.zhang@gmail.com wbaehr@hsc.utah.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism*; D004596:Electroretinography; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000378:metabolism*; D019204:GTP-Binding Proteins; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D017368:Protein Prenylation; D021381:Protein Transport; D011817:Rabbits; D012174:Retinitis Pigmentosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C072178:RP2 protein, human; D006160:Guanosine Triphosphate; D051606:G-Protein-Coupled Receptor Kinase 1; C496762:Grk1 protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D019204:GTP-Binding Proteins; C490248:Arl3 protein, mouse; D020727:ADP-Ribosylation Factors
keywords: ARL3; PDE6D; RP2; XLRP; rod-cone dystrophy