Eye disorders

MERTK-related retinitis pigmentosa; Leber congenital amaurosis; Retinitis pigmentosa 38

Retinitis pigmentosa (RP) is an inherited degenerative eye disease characterized by the progressive loss of photoreceptor cells and/or the retinal pigmented epithelium (RPE) of the retina and the aberrant deposition of retinal pigment. Affected individuals often display defective light-to-dark or dark-to-light adaptation, night blindness (nyctalopia), and peripheral visual field vision loss (tunnel vision). Leber congenital amaurosis is an eye disease that predominately affects the retina. Affected individuals display severe visual defects, photophobia, nystagmus (involuntary eye movement), and far-sightedness. MER also plays a role in the retinal pigmented epithelium (RPE) in the regulation of phagocytotic activity, which mainly functions to prevent the aberrant accumulation of fragments shed by the rod outer segments. Several mutations in the MER gene have been observed in patients with RP, including a 5-bp deletion mutation (2070delAGGAc) resulting in a frameshift, a splice site mutation in the intron 10 splice acceptor site, termination mutations (R651X, R775X), a truncating transversion mutation (1289+1G-T), a 9-kb deletion mutation encompassing exon 8 and part of intron 7 and 8, and a 91-kb deletion encompassing exons 1-7 of the gene. These mutations observed in RP patients are associated with a loss-of-function of MER phosphotransferase activity. In animal studies, a small inactivating deletion mutation in the MER gene was found in a rat model of inherited retinal degeneration characterized by the failure of the retinal pigmented epithelium (RPE) to phagocytose fragments shed by the outer segments, resulting in photoreceptor cell death. Furthermore, mice lacking MER expression displayed inefficient clearance of apoptotic debris by macrophages in the RPE, leading to the aberrant accumulation of rod fragments. Sub-retinal injection of an adenovirus carrying MER into the retina of rats with retinal degeneration was sufficient to correct the retinal dystrophy phenotype, resulting in the preservation of photoreceptor cells and restoring efficient phagocytosis capability to the RPE. Therefore, loss-of-function mutations in the MER gene are suggested to be the underlying cause of various forms of retinal degeneration, such as that seen in RP.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +54, p<0.053); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +177, p<0.001); Oral squamous cell carcinomas (OSCC) (%CFC= +63, p<0.016); and Vulvar intraepithelial neoplasia (%CFC= -58, p<0.001). The COSMIC website notes an up-regulated expression score for MERTK in diverse human cancers of 445, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.08 % in 25518 diverse cancer specimens. This rate is very similar (+ 8% higher) to the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.58 % in 805 skin cancers tested; 0.41 % in 1093 large intestine cancers tested; 0.34 % in 502 urinary tract cancers tested; 0.18 % in 602 endometrium cancers tested; 0.13 % in 1941 lung cancers tested.

None > 5 in 20,801 cancer specimens

Only 2 deletions, and no insertions or complex mutations are noted on the COSMIC website.