title: Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium.
abstract: Mutations in the ubiquitously expressed pre-mRNA processing factors 3, 8, and 31 (PRPF3, PRPF8, and PRPF31) cause nonsyndromic dominant retinitis pigmentosa in humans, an inherited retinal degeneration. It is unclear what mechanisms, or which cell types of the retina, are affected. Transgenic mice with the human mutations in these genes display late-onset morphological changes in the retinal pigment epithelium (RPE). To determine whether the observed morphological changes are preceded by abnormal RPE function, we investigated its phagocytic function in Prpf3(T494M/T494M), Prpf8(H2309P/H2309P), and Prpf31(+/-) mice. We observe decreased phagocytosis in primary RPE cultures from mutant mice, and this is replicated by shRNA-mediated knockdown of PRPF31 in human ARPE-19 cells. The diurnal rhythmicity of phagocytosis is almost lost, indicated by the marked attenuation of the phagocytic burst 2 hours after light onset. The strength of adhesion between RPE apical microvilli and photoreceptor outer segments also declined during peak adhesion in all mutants. In all models, at least one of the receptors involved in binding and internalization of shed photoreceptor outer segments was subjected to changes in localization. Although the mechanism underlying these changes in RPE function is yet to be elucidated, these data are consistent with the mouse RPE being the primary cell affected by mutations in the RNA splicing factors, and these changes occur at an early age.
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Farkas
authors.affiliation: Vision Institute, INSERM, U968, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, CNRS, UMR_7210, Paris, France.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Lew
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Sousa
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Vision Institute, INSERM, U968, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, CNRS, UMR_7210, Paris, France.
authors.forename: Kinga
authors.initials: K
authors.lastname: Bujakowska
authors.affiliation: Vision Institute, INSERM, U968, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, CNRS, UMR_7210, Paris, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chatagnon
authors.affiliation: Vision Institute, INSERM, U968, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, CNRS, UMR_7210, Paris, France; Institute of Ophthalmology, University College London, London, United Kingdom; Andalusian Center of Molecular Biology and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Sevilla, Spain.
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Electronic address: eric_pierce@meei.harvard.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.affiliation: Vision Institute, INSERM, U968, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, CNRS, UMR_7210, Paris, France. Electronic address: emeline.nandrot@inserm.fr.
authors.forename: Emeline F
authors.initials: EF
authors.lastname: Nandrot
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010587:Phagocytosis; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000473:pathology* / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics*
chemical_list: D005136:Eye Proteins; C454222:PRPF31 protein, human; C555603:PRPF31 protein, mouse; C433464:Prp8 protein, mouse; C532027:Prpf3 protein, mouse; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear
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