title: REEP6 mediates trafficking of a subset of Clathrin-coated vesicles and is critical for rod photoreceptor function and survival.
abstract: In retinal photoreceptors, vectorial transport of cargo is critical for transduction of visual signals, and defects in intracellular trafficking can lead to photoreceptor degeneration and vision impairment. Molecular signatures associated with routing of transport vesicles in photoreceptors are poorly understood. We previously reported the identification of a novel rod photoreceptor specific isoform of Receptor Expression Enhancing Protein (REEP) 6, which belongs to a family of proteins involved in intracellular transport of receptors to the plasma membrane. Here we show that loss of REEP6 in mice (Reep6-/-) results in progressive retinal degeneration. Rod photoreceptor dysfunction is observed in Reep6-/- mice as early as one month of age and associated with aberrant accumulation of vacuole-like structures at the apical inner segment and reduction in selected rod phototransduction proteins. We demonstrate that REEP6 is detected in a subset of Clathrin-coated vesicles and interacts with the t-SNARE, Syntaxin3. In concordance with the rod degeneration phenotype in Reep6-/- mice, whole exome sequencing identified homozygous REEP6-E75K mutation in two retinitis pigmentosa families of different ethnicities. Our studies suggest a critical function of REEP6 in trafficking of cargo via a subset of Clathrin-coated vesicles to selected membrane sites in retinal rod photoreceptors.
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Shobi
authors.initials: S
authors.lastname: Veleri
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nellissery
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Bibhudatta
authors.initials: B
authors.lastname: Mishra
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Souparnika H
authors.initials: SH
authors.lastname: Manjunath
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brooks
authors.affiliation: Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lijin
authors.initials: L
authors.lastname: Dong
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Visual Function Core, 5Biological Imaging Core.
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Gao
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Sergeev
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou 325027, China and.
authors.forename: Xiu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou 325027, China and.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou 325027, China and.
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou 325027, China and.
authors.forename: Zi-Bing
authors.initials: ZB
authors.lastname: Jin
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Rinki
authors.initials: R
authors.lastname: Ratnapriya
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Neurobiology Neurodegeneration and Repair Laboratory.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000818:Animals; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics; D055537:Light Signal Transduction; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D050765:Qa-SNARE Proteins / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics; D050600:SNARE Proteins / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D050765:Qa-SNARE Proteins; C000602312:REEP6 protein, mouse; D050600:SNARE Proteins