title: A murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration.
abstract: Mutations in the RP1 gene can cause retinitis pigmentosa. We identified a spontaneous L66P mutation caused by two adjacent point mutations in the Rp1 gene in a colony of C57BL/6J mice. Mice homozygous for the L66P mutation exhibited slow, progressive photoreceptor degeneration throughout their lifespan. Optical coherence tomography imaging found abnormal photoreceptor reflectivity at 1 month of age. Histology found shortening and disorganization of the photoreceptor inner and outer segments and progressive thinning of the outer nuclear layer. Electroretinogram a- and b-wave amplitudes were decreased with age. Western blot analysis found that the quantity and size of the mutated retinitis pigmentosa 1 (RP1) protein were normal. However, immunohistochemistry found that the mutant Rp1 protein partially mislocalized to the transition zone of the shortened axonemes. This mutation disrupted colocalization with cytoplasmic microtubules in vitro. In conclusion, the L66P mutation in the first doublecortin domain of the Rp1 gene impairs Rp1 protein localization and function, leading to abnormalities in photoreceptor outer segment structure and progressive photoreceptor degeneration. This is the first missense mutation in Rp1 shown to cause retinal degeneration. It provides a unique, slowly progressive photoreceptor degeneration model that mirrors the slow degeneration kinetics in most patients with retinitis pigmentosa.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Delu
authors.initials: D
authors.lastname: Song
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Steve
authors.initials: S
authors.lastname: Grieco
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Allan
authors.initials: A
authors.lastname: Hunter
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sally
authors.initials: S
authors.lastname: Chu
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology, Second Hospital of Jilin University, Changchun, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert A
authors.initials: RA
authors.lastname: DeAngelis
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Shi
authors.affiliation: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: jdunaief@upenn.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
mesh_terms: D000818:Animals; D054468:Axoneme / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010786:Photoreceptor Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; C120042:RP1 protein, human; C497821:RP1 protein, mouse
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