Disease relevance of MERTK

• Our results suggest that retinal degeneration in these individuals is due to apparently complete paternal isodisomy involving reduction to homoallelism for RPE65 or MERTK loss-of-function alleles [1].
• MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells [2].
• CONCLUSION: Our findings suggest that polymorphisms in MERTK might be one of the genetic risk factors for presenting leucopenia and lymphopenia in SLE patients [3].
• OBJECTIVE: The MER receptor tyrosine kinase (MERTK) gene is critical for the efficient clearance of apoptotic cells and has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE) [3].
• PURPOSE: To determine whether mutations in the MERTK gene are present in Japanese patients with autosomal recessive retinitis pigmentosa (arRP) [4].

High impact information on MERTK

• Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa [5].
• Mutation of a receptor tyrosine kinase gene, Mertk, in the Royal College of Surgeons (RCS) rat results in defective phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) and retinal degeneration [5].
• At least six new families of MER repeats and one pseudogene are intercalated within and between the Alu clusters [6].
• Although the enzyme from Streptomyces lividans has no addition, from Pseudomonas aeruginosa Tn501 and Bacillus sp. strain RC607 it has one and two copies respectively of a domain of 80-85 residues, highly homologous to MerP, the periplasmic component of proteins encoded by the mer operon [7].
• Complementary DNA (cDNA) clones corresponding to the major histocompatibility (MHC) class III antigen, complement protein C2, have been isolated from human liver cDNA libraries with the use of a complex mixture of synthetic oligonucleotides (17 mer) that contains 576 different oligonucleotide sequences [8].

Chemical compound and disease context of MERTK

• BACKGROUND/AIM: MERTK, a tyrosine kinase receptor protein expressed by the retinal pigment epithelium (RPE), is mutated in both rodent models and humans affected by retinal disease [9].
• Knockout of the mer gene protected mice from collagen/epinephrine-induced pulmonary thromoembolism and inhibited ferric chloride-induced thrombosis in vivo [10].
• Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine-induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disorders [11].
• Forty patients with advanced gastrointestinal cancer, all previous chemotherapy failures, were treated with a methanol extraction residue of Bacillus Calmette-Guérin (MER) alone, administered intradermally in either weekly or every-4-week schedules [12].
• We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-beta 1-mRNA and TGF-beta 2-mRNA [13].

Biological context of MERTK

• Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively [1].
• In contrast, C844 MERTK was expressed at low levels and did not stimulate tyrosine phosphorylation [2].
• CONCLUSIONS: The present study reports the identification of R844C, the first putative pathogenic MERTK missense mutation that results in severe retinal degeneration with childhood onset when in compound heterozygous form with a R722X allele [2].
• METHODS: MERTK missense variants identified by single-strand conformational polymorphism (SSCP) and sequence analysis were introduced into expression constructs and used to transfect HEK293T cells [2].
• We investigated the genetic polymorphisms in MERTK to evaluate it as a potential candidate gene for a host genetic study of SLE and clinical manifestations in patients with SLE [3].

Anatomical context of MERTK

• In transfected HEK293Tcells, wild-type (wt) and W865 MERTK were expressed at equivalent levels and present in the plasma membrane, stimulated tyrosine phosphorylation, and induced significant rounding of the cell bodies [2].
• In this report, we show that R induces expression of the cellular C-mer gene in a variety of cell lines [14].
• C-mer is required for phagocytosis of apoptotic debris by monocytes/macrophages and retinal pigment epithelial cells and is capable of producing an antiapoptotic signal [14].
• Since the ryk designation has been used to name another tyrosine kinase and an analysis of RNA expression demonstrated that this novel human kinase is expressed in monocytes and tissues of epithelial and reproductive origin, we have designated our novel protooncogene c-mer [15].
• Tail bleeding times, coagulation parameters, and peripheral blood cell counts in mer-deficient mice were similar to wild-type mice [10].

Associations of MERTK with chemical compounds

• Platelets derived from mer-deficient mice had decreased platelet aggregation in responses to low concentrations of collagen, U46619, and PAR4 thrombin receptor agonist peptide in vitro [10].
• The phenoxazine/C-5 propynyl U 7-mer S-ON showed dose-dependent, sequence-specific, and target-selective antisense activity following microinjection into cells [16].
• We now report that a 21-mer peptide, in which a tryptophan has been incorporated at the N terminus of the 20th mer, can replace the R2 subunit and initiate nucleotide reduction by photoinitiated radical generation [17].
• Forty patients with histologically confirmed neoplastic diseases were treated with the methanol extraction residue of Bacillus Calmette-Guérin (MER) [18].
• Eighty-four patients with advanced cancer refractory to conventional therapeutic modalities were randomly assigned in double-blind fashion to one of three intradermal treatment regimens: "high"-dose methanol extraction residue fraction of Bacillus Calmette-Guérin (MER) (2.0 mg); "low"-dose MER (0.5 mg); or 0.9% NaCl solution placebo [19].

Regulatory relationships of MERTK

• C-mer is a receptor tyrosine kinase activated by the ligand Gas6 [14].

Other interactions of MERTK

• We identified an apparently homozygous loss-of-function mutation of RPE65 (1p31) in one retinal dystrophy patient and an apparently homozygous loss-of-function mutation of MERTK (2q14.1) in a second retinal dystrophy patient [1].
• MATERIALS AND METHODS: In this report, we further investigate the protein expression of the whole axl receptor tyrosine-kinase family (axl/ufo, nyk/mer and sky/rse) by immunohistochemistry and their clinicopathological associations [20].

Analytical, diagnostic and therapeutic context of MERTK

• This study provides strong support for the development of AAV-mediated gene therapy for RP caused by mutations in the MERTK gene [21].
• We report the chromosomal localization of the rat c-mer gene in the cytogenetic bands 3q35-36, based on genetic analysis and radiation hybrid mapping [22].
• Assignment of protooncogene MERTK (a.k.a. c-mer) to human chromosome 2q14.1 by in situ hybridization [23].
• METHODS AND RESULTS: Using RT-PCR and Western blot analysis we found that mer was the predominantly expressed subtype in mouse and human platelets, whereas axl and rse were not detected [10].
• Nonspecific immunotherapy with MER was administered in five sites at 100 micrograms or at the lowest tenfold dilution that produced a 1-cm indurated lesion [24].

References