Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat

Vertebrate photoreceptor cells are the basic sensory apparatus of the retin a, capable of converting the energy of absorbed photons into neuronal signa ls, The proximal portions of mammalian photoreceptor outer segments are syn thesized daily by cell bodies, and outer segment tips are shed with a circa dian rhythm, resulting in a complete turnover of outer segments about every 9 days, The shed outer segments are phagocytosed by adjacent retinal pigme nt 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 pha gocytose 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 a nd third coding exons, leading to a frameshift and a translation terminatio n signal 20 codons after the AUG, The concordance of these and other data i ndicate that Mertk is probably the gene for rdy, Our results provide geneti c evidence for an essential role of a receptor tyrosine kinase in a special ized form of phagocytosis and suggest a molecular model for ingestion of ou ter segments by RPE cells.