title: Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat.
abstract: Vertebrate photoreceptor cells are the basic sensory apparatus of the retina, capable of converting the energy of absorbed photons into neuronal signals. The proximal portions of mammalian photoreceptor outer segments are synthesized daily by cell bodies, and outer segment tips are shed with a circadian rhythm, resulting in a complete turnover of outer segments about every 9 days. The shed outer segments are phagocytosed by adjacent retinal pigment epithelial (RPE) cells, and metabolites are recycled to photoreceptors. The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the RPE fails to phagocytose shed outer segments, and photoreceptor cells subsequently die. We have used a positional cloning approach to study the rdy (retinal dystrophy) locus of the RCS rat. Within a 0.3 cM genetic inclusion interval, we have discovered a small deletion of RCS DNA that disrupts the gene encoding the receptor tyrosine kinase Mertk. The deletion includes the splice acceptor site upstream of the second coding exon of Mertk and results in a shortened transcript that lacks this exon. The aberrant transcript joins the first and third coding exons, leading to a frameshift and a translation termination signal 20 codons after the AUG. The concordance of these and other data indicate that Mertk is probably the gene for rdy. Our results provide genetic evidence for an essential role of a receptor tyrosine kinase in a specialized form of phagocytosis and suggest a molecular model for ingestion of outer segments by RPE cells.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305-5120, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: D'Cruz
authors.forename: D
authors.initials: D
authors.lastname: Yasumura
authors.forename: J
authors.initials: J
authors.lastname: Weir
authors.forename: M T
authors.initials: MT
authors.lastname: Matthes
authors.forename: H
authors.initials: H
authors.lastname: Abderrahim
authors.forename: M M
authors.initials: MM
authors.lastname: LaVail
authors.forename: D
authors.initials: D
authors.lastname: Vollrath
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D015870:Gene Expression; D005819:Genetic Markers; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020161:Physical Chromosome Mapping; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011995:Recombination, Genetic; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000076202:c-Mer Tyrosine Kinase
chemical_list: D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; C490765:Mertk protein, rat; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase