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

TLDR

Photoreceptor cells convert photons into neuronal signals, and their outer segments are continuously synthesized and shed every ~9 days, a process normally cleared by retinal pigment epithelial phagocytosis; in the Royal College of Surgeons rat, this phagocytic failure leads to photoreceptor death and retinal degeneration. The study employed positional cloning to investigate the rdy locus responsible for retinal dystrophy in the RCS rat. Positional cloning narrowed the rdy locus to a 0.3 cM interval. A small deletion disrupting the Mertk receptor tyrosine kinase gene was identified within this interval, producing a truncated transcript lacking exon 2 and a premature stop codon, thereby establishing Mertk as the rdy gene and highlighting its essential role in retinal pigment epithelial phagocytosis of photoreceptor outer segments.

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.