title: Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization.
abstract: The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higher-order organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44160, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kolesnikov
authors.forename: Beata
authors.initials: B
authors.lastname: Jastrzebska
authors.forename: Debarshi
authors.initials: D
authors.lastname: Mustafi
authors.forename: Osamu
authors.initials: O
authors.lastname: Sawada
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Christel
authors.initials: C
authors.lastname: Genoud
authors.forename: Andreas
authors.initials: A
authors.lastname: Engel
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005091:Exons; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D010587:Phagocytosis / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D015293:Transducin / Q000235:genetics / Q000378:metabolism
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C488949:Gnat1 protein, mouse; D012243:Rhodopsin; D015293:Transducin