Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa

Gal, Andreas; Li, Yun; Thompson, Debra A.; Weir, Jessica; Orth, Ulrike; Jacobson, Samuel G.; Apfelstedt-Sylla, Eckart; Vollrath, Douglas

doi:10.1038/81555

Cited by 568 publications

(454 citation statements)

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“…Different from the SI-induced degeneration in rabbits, the retinal degeneration in RCS rat results from impairment of phagocytosis of photoreceptor outer segment, and not from the decrease in the number of the RPE cells. 17 Thus, even if TFPI-2 stimulated the growth of the RPE cells, it is unlikely that the resultant increase in the number of the functionally abnormal RPE cells could contribute to the decreased degeneration of the neural retina. Thus, our results imply that TFPI-2 ameliorates the retinal degeneration, not by the growth stimulatory effect but by the trophic effect, at least in RCS rats.…”

Section: Discussionmentioning

confidence: 99%

“…16 In some groups of retinal degeneration, the RPE is affected primarily, and the degeneration in the neural retina is the secondary process. 17,18 So it is possible that TFPI-2 can ameliorate the progressive loss of visual function due to the loss or dysfunction of the RPE. In this study, we investigated the effects of TFPI-2 on the RPE function after the retinal degeneration was induced by sodium iodate(SI) in Dutch rabbits, using the electrophysiological analysis.…”

Section: Introductionmentioning

confidence: 99%

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Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

Obata

Yanagi

Tamaki

et al. 2004

Eye

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Purpose To investigate the in vivo effects of tissue factor pathway inhibitor 2 (TFPI-2), which stimulates proliferation of retinal pigment epithelial cells, but not the proliferation of fibroblast and vascular endothelial cells in vitro, on retinal degeneration using a sodium-iodate (SI)-induced model in rabbits and Royal Collage of Surgeons (RCS) rats. Methods 79 mg of recombinant TFPI-2 (rTFPI-2) or vehicle alone was injected intravitreously to 18 eyes of 12 pigmented rabbits a day after 20 mg/kg of SI was intravenously administered. Retinal function was assessed 4, 7, 14, and 21 days after the injection by analysing amplitudes of the c-wave of a bright flash electroretinogram. Additionally, 10 mg of rTFPI-2 or vehicle alone was injected intravitreously to 11 eyes of RCS rats at both 3 and 4 weeks old, then the retina was examined histologically at 5 weeks old. Results The rTFPI-2-treated eyes in rabbits showed a significantly less decrease in the relative amplitude of the c-wave than control eyes on days 4 and 7. The thickness of the outer nuclear layer was significantly thicker and the vacuole in the photoreceptor layer was less frequently observed in the rTFPI-2-treated RCS rats than the controls. Conclusions Intravitreal injection of TFPI-2 rescues SI-induced retinal degeneration in rabbits and naturally occurring retinal degeneration in RCS rats at least partly. These results may suggest that this compound can be utilized in the treatment of retinal degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

Obata

Yanagi

Tamaki

et al. 2004

Eye

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“…76 The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the RPE to phagocytose shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. The defect, which has also been described in patients with retinitis pigmentosa, 77 results from a mutation in the mertk gene, which is normally expressed in the RPE. The first demonstration of successful rescue of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration was achieved by recombinant adenovirus-mediated gene transfer to the RPE.…”

Section: Gene Replacement Therapymentioning

confidence: 91%

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Rolling

2004

Gene Ther

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“…As noted above, degeneration of photoreceptors was originally noted in mice lacking all three TAM receptors 20 . However, this was subsequently found -in rats, mice and humans -to be due to mutations of the Mer gene alone [37][38][39][40][41] . A long-studied inherited form of retinitis pigmentosa in rats [37][38][39] , and a more recently described inherited form of the disease in humans 40,41 , are both due to Mer gene mutations.…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

“…However, this was subsequently found -in rats, mice and humans -to be due to mutations of the Mer gene alone [37][38][39][40][41] . A long-studied inherited form of retinitis pigmentosa in rats [37][38][39] , and a more recently described inherited form of the disease in humans 40,41 , are both due to Mer gene mutations. MER and TYRO3 have been localized to the apical tips of the RPE cell processes that penetrate the photoreceptor outer segment layer and pinch off the distal ends of the outer segments 10 .…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa

Cited by 568 publications

References 13 publications

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Immunobiology of the TAM receptors

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