* 604705

MER TYROSINE KINASE PROTOONCOGENE; MERTK


HGNC Approved Gene Symbol: MERTK

Cytogenetic location: 2q13     Genomic coordinates (GRCh38): 2:111,898,607-112,029,561 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q13 Retinitis pigmentosa 38 613862 AR 3

TEXT

Cloning and Expression

By screening a human B-lymphoblastoid lambda-gt11 expression library with polyclonal antiphosphotyrosine antisera, Graham et al. (1994) obtained a cDNA clone encoding a novel tyrosine kinase, MERTK, which the authors designated c-mer. They subsequently obtained genomic clones from a human placenta genomic library. MERTK encodes a 984-amino acid protein with a calculated molecular mass of 109 kD. It shares 71% amino acid sequence identity with the chicken retroviral oncogene v-ryk. The protein has a putative transmembrane segment, a tyrosine kinase domain, several N-glycosylation sites, and tyrosine phosphorylation sites. MERTK shows similarity to AXL (109135), another tyrosine kinase, in that it contains 2 amino terminal immunoglobulin domains and 2 membrane proximal fibronectin type III domains in its extracellular region as well as the kinase signature sequence KWIAIES. MERTK is not expressed in normal B- and T-lymphocytes but, unlike AXL, is expressed in numerous neoplastic B- and T-cell lines. Transcripts for this novel receptor-like tyrosine kinase were detected in normal peripheral blood monocytes, bone marrow, and tissues of epithelial and reproductive origin. One alternatively spliced transcript, which contained an insert in the membrane proximal region, could encode for a truncated, soluble receptor.


Gene Function

Loss of function of the 3 TAM receptors, Tyro3 (600341), Axl, and Mer, results in profound dysregulation of the immune response in mice (see ANIMAL MODEL). By analyzing TAM function in the dendritic cell subset of mouse antigen-presenting cells, Rothlin et al. (2007) found that TAM inhibited inflammation through an essential stimulator of inflammation, Ifnar (107450), and its associated transcription factor, Stat1 (600555). Toll-like receptor (TLR; see 601194) induction of Ifnar-Stat1 signaling upregulated the TAM system, which, in turn, induced the cytokine and TLR suppressors Socs1 (603597) and Socs3 (604176). Rothlin et al. (2007) concluded that cytokine-dependent activation of TAM signaling diverts a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.

Png et al. (2012) demonstrated that endogenous miR126 (611767), a miRNA silenced in a variety of human cancers, non-cell-autonomously regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. It suppresses metastatic endothelial recruitment, metastatic angiogenesis, and metastatic colonization through coordinate targeting of IGFBP2 (146731), PITPNC1 (605134), and MERTK--novel proangiogenic genes and biomarkers of human metastasis. Insulin-like growth factor binding protein-2 (IGFBP2) secreted by metastatic cells recruits endothelia by modulating IGF1 (147440)-mediated activation of the IGF type-I receptor (147370) on endothelial cells, whereas MERTK receptor cleaved from metastatic cells promotes endothelial recruitment by competitively antagonizing the binding of its ligand GAS6 to endothelial MERTK receptors. Coinjection of endothelial cells with breast cancer cells non-cell-autonomously rescues their miR126-induced metastatic defect, revealing a novel and important role for endothelial interactions in metastatic initiation. Through loss-of-function and epistasis experiments, Png et al. (2012) delineated a miRNA regulator network's individual components as novel and cell-extrinsic regulators of endothelial recruitment, angiogenesis, and metastatic colonization. The authors also identified the IGFBP2/IGF1/IGF1R and GAS6/MERTK signaling pathways as regulators of cancer-mediated endothelial recruitment.

Chung et al. (2013) reported a role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 (612453) and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways failed to refine their retinogeniculate connections normally and retained excess functional synapses. Finally, Chung et al. (2013) showed that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. Chung et al. (2013) concluded that their studies revealed a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, and identified MEGF10 and MERTK as critical proteins in the synapse remodeling underlying neural circuit refinement.

Paolino et al. (2014) demonstrated that genetic deletion of the E3 ubiquitin ligase CBLB (604491) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumors. The TAM tyrosine kinase receptors TYRO3, AXL, and MERTK were identified as ubiquitylation substrates for CBLB. Treatment of wildtype NK cells with a small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing antimetastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. Paolino et al. (2014) further reported that the anticoagulant warfarin exerts antimetastatic activity in mice via Cblb/TAM receptors in NK cells, providing a molecular explanation for the effect of warfarin to reduce tumor metastases in rodent models. Paolino et al. (2014) concluded that this novel TAM/CBLB inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

Fourgeaud et al. (2016) demonstrated that the TAM receptor tyrosine kinases Mer and Axl regulate the microglial functions of damage sensing and routine noninflammatory clearance of dead brain cells. Fourgeaud et al. (2016) found that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the central nervous system (CNS), and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 (600441) and protein S (176880). Using live 2-photon imaging, the authors demonstrated that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Fourgeaud et al. (2016) also showed that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson disease (168600). Fourgeaud et al. (2016) concluded that these results established TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.


Mapping

By fluorescence in situ hybridization, Weier et al. (1999) mapped the MERTK gene to chromosome 2q14.1.


Molecular Genetics

Gal et al. (2000) screened the MERTK gene, the human ortholog of the RCS rat retinal dystrophy gene, in 328 DNA samples from individuals with various retinal dystrophies and found 3 mutations in 3 unrelated individuals with retinitis pigmentosa (604705.0001-604705.0003). This finding was the first conclusive evidence implicating the retinal pigment epithelium (RPE) phagocytosis pathway in human retinal disease. They examined each of the 19 coding exons of MERTK and adjacent splice sites for evidence of mutation by SSCP or direct sequencing.

Thompson et al. (2002) found paternal isodisomy for chromosome 2 in a woman with retinitis pigmentosa and an apparently homozygous MERTK mutation, IVS10-2A-G (604705.0002), that was present in heterozygous form in her unaffected father but was not present in her mother. Analysis of haplotypes indicated the absence of the maternal allele for all informative markers on chromosome 2. This provided the first evidence that chromosome 2 carries no paternally imprinted genes that have a major effect on phenotype.

In 5 sibs from a consanguineous Moroccan family with retinal dystrophy, Ebermann et al. (2007) identified homozygosity for a splice site mutation in the MERTK gene (604705.0004).

In affected members of 2 consanguineous Middle Eastern families with retinal dystrophy, Mackay et al. (2010) identified homozygosity for a deletion involving exon 8 of the MERTK gene (604705.0005). In a Caucasian man with childhood-onset rod-cone dystrophy, the authors identified compound heterozygosity for the known MERTK nonsense mutation R651X (604705.0003) and a splice site mutation (604705.0006).

In 7 of 21 cases of RP in the Faroe Islands, Ostergaard et al. (2011) identified a 91-bp deletion in the MERTK gene (604705.0007).

In a consanguineous Moroccan family with the rod-cone dystrophy type of RP, Ksantini et al. (2012) identified homozygosity for a nonsense mutation in the tyrosine kinase domain of MERTK (R775X; 604705.0008).


Animal Model

The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the retinal pigment epithelium (RPE) fails to phagocytose shed outer segments, and photoreceptor cells subsequently die. D'Cruz et al. (2000) used a positional cloning approach to localize the rdy (retinal dystrophy) locus of the RCS rat to within a 0.3-cM interval on rat chromosome 3. The authors discovered a small deletion of RCS DNA that disrupted Mertk. The deletion resulted in a shortened transcript with a termination signal 20 codons after the AUG. The authors concluded that Mertk is probably the gene for rdy.

Camenisch et al. (1999) generated a functional knockout mouse with a truncation of the Mer cytoplasmic tail (Mer-kd). Scott et al. (2001) showed these mice to have macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimeric mice reconstituted with bone marrow from wildtype animals. Primary macrophages isolated from Mer-kd mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor (see 605484)-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in Mer-kd mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. Scott et al. (2001) concluded that this may have implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (152700). Lu et al. (1999) generated mice deficient in Mertk, Axl, and Tyro3. Triply deficient male mice were infertile due to degenerative spermatogenesis. In addition, triply deficient mice were blind and had neurologic abnormalities and splenomegaly owing to increased numbers of apoptotic cells. Scott et al. (2001) suggested that the removal of apoptotic cells mediated partly by the cytoplasmic signaling domain of Mer may be critical to the maintenance of tissue homeostasis and the prevention of autoimmunity.

Regulation of lymphocyte numbers is mediated by cytokines signaling through receptors coupled to cytoplasmic protein-tyrosine kinases. Lu and Lemke (2001) generated mice deficient in Mertk, Axl, and Tyro3. Like their ligands, GAS6 (600441) and PROS1 (176880), these receptors are widely expressed in monocytes and macrophages but not in B or T lymphocytes. Although the peripheral lymphoid organs of mutant mice were indistinguishable from those of wildtype mice at birth, by 4 weeks of age spleens and lymph nodes grew at elevated rates. This was primarily due to the hyperproliferation of constitutively activated B and T cells, particularly CD4-positive T cells, with ectopic colonies in every adult organ examined. All triple mutants developed autoimmunity with symptoms histologically similar to human rheumatoid arthritis (180300), pemphigus vulgaris (169610), and systemic lupus erythematosus, and were characterized by antibodies against normal cellular antigens, including phospholipids and double-stranded DNA. Females were particularly prone to thromboses and recurrent fetal loss. Flow cytometric analysis demonstrated that wildtype B and T cells underwent multiple rounds of cell division after injection into mutant mice and that their antigen-presenting cells expressed elevated levels of activation markers. Lu and Lemke (2001) proposed that the cells that initiate lymphoproliferation and autoimmunity in the Tyro3 family mutants were the macrophages and dendritic cells that normally express the 3 receptor genes.

Vollrath et al. (2001) sought to determine whether gene transfer of MERTK to an RCS rat retina would result in correction of the phagocytosis defect in the retinal pigment epithelium and preservation of photoreceptors. They used subretinal injection of a recombinant replication-deficient adenovirus encoding rat MERTK to deliver the gene to the eyes of young RCS rats. Electrophysiologic, histologic, and ultrastructural assessment indicated a correction of the retinal dystrophy phenotype. Results provided definitive evidence that mutation of MERTK underlies the RCS retinal dystrophy phenotype. Vollrath et al. (2001) stated that this was the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE.

Zhang et al. (2003) examined the retinal distribution of the chondroitin sulfate proteoglycan neurocan (600826) in RCS rats. Neurocan accumulation in association with the retinal vasculature did not correlate with photoreceptor cell loss, because similar deposits were not observed in the retinas of rhodopsin mutant rats. In RCS rats, however, neurocan immunostaining was seen in association with retinal vessels from postnatal day 15 onward. The authors hypothesized that with time, the accumulated perivascular neurocan might, via interaction with other matrix molecules, modulate at least some of the vascular alterations observed in the RCS rat model.

Angelillo-Scherrer et al. (2005) generated mice lacking 1 of the 3 Gas6 receptors: Tyro3, Axl, or Mertk. Loss of any 1 of the Gas6 receptors or delivery of a soluble extracellular domain of Axl that traps Gas6 protected the mice against life-threatening thrombosis. Loss of a Gas6 receptor did not prevent initial platelet aggregation but impaired subsequent stabilization of platelet aggregates, at least in part by reducing outside-in signaling and platelet granule secretion. Gas6, through its receptors, activated PI3K and Akt (see 164730) and stimulated tyrosine phosphorylation of the beta-3 integrin (173470), thereby amplifying outside-in signaling via alpha-IIb (607759)-beta-3.

Khan et al. (2013) found that Mer -/- mice showed accumulation of apoptotic cells (ACs) primarily in germinal centers (GCs), where Mer is normally expressed on macrophages, but not on B or T cells. AC accumulation in GCs of Mer -/- mice led to augmented antibody-forming cell and IgG2 responses persisting for at least 80 days. The enhanced responses were due to increased activation and proliferation of B cells and Cd4 (186940)-positive T-helper (Th) cells. Secondary total IgG and IgG2 responses were also increased in Mer -/- mice. Consistent with the elevated levels of IgG2 antibodies, Mer -/- mice also had an increased percentage of Ifng (147570)-producing Cd4 cells and increased levels of Th1 (i.e., IL2, 147680, and Ifng) and proinflammatory (i.e., Tnf, 191160, and IL6, 147620) cytokines. Khan et al. (2013) concluded that Mer deficiency induces prolonged accumulation of ACs in GCs, resulting in dysregulation of GC B-cell and Cd4-positive Th-cell responses and Th1 cytokine production, leading to alteration of B-cell tolerance and development of autoantibodies.


ALLELIC VARIANTS ( 8 Selected Examples):

.0001 RETINITIS PIGMENTOSA 38

MERTK, 5-BP DEL, NT2070
  
RCV001001159...

In a sample from a 45-year-old man with retinitis pigmentosa (RP38; 613862) who was the offspring of a consanguineous union, Gal et al. (2000) found an apparently homozygous 5-bp deletion in exon 15 (2070delAGGAC) of the MERTK gene. He had onset of night blindness and poor vision in early childhood and at the time of study had only a small central island of remaining vision. Two children were heterozygous. The mutation resulted in a frameshift after codon 690, predicting inclusion of 41 MERTK-unrelated amino acid residues before premature termination. This predicted mutant protein would lack nearly one-third of the wildtype residues, including most of the conserved tyrosine kinase domain.


.0002 RETINITIS PIGMENTOSA 38

MERTK, IVS10AS, A-G, -2
  
RCV000005732...

In a sample from a 34-year-old woman with retinitis pigmentosa (RP38; 613862) whose unaffected parents were not known to be related, Gal et al. (2000) found an apparently homozygous A-to-G transition in the intron 10 splice acceptor site of the MERTK gene. She had onset of night blindness and poor vision in early childhood and at the time of study had only a small central island of remaining vision. The splice mutation, which ablated a consensus nucleotide (-2) of the acceptor site, was predicted to result in aberrant splicing of the MERTK transcript. The proband's father, but not her mother, was heterozygous for the splice site change. Further studies demonstrated that the proband was disomic for the paternal homolog (Thompson et al., 2002).


.0003 RETINITIS PIGMENTOSA 38

MERTK, ARG651TER
  
RCV000005733...

In a sample from a 21-year-old woman with retinitis pigmentosa (RP38; 613862) who had had poor vision as a child, Gal et al. (2000) found a heterozygous premature termination codon (arg651 to ter; R651X) in the MERTK gene. At age 12, she had complaints of night blindness. A second mutation was not found in this individual by direct sequencing of exons 1 through 19 of the MERTK gene.

In a 22-year-old Caucasian man with childhood-onset rod-cone dystrophy and early macular atrophy, Mackay et al. (2010) identified compound heterozygosity for the R651X mutation in the MERTK gene, and a G-A transition in intron 1 (61+1G-A; 604705.0006), predicted to disrupt the donor splice site. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 100 ethnically matched controls.


.0004 RETINITIS PIGMENTOSA 38

MERTK, IVS16DS, G-T, +1
  
RCV000005734...

In 5 sibs from a consanguineous Moroccan family with retinal dystrophy (RP38; 613862), Ebermann et al. (2007) identified a homozygous G-to-T transversion in intron 16 (2189+1G-T), resulting in the skipping of exon 16 and truncation of the protein to 696 residues. Ebermann et al. (2007) classified the retinal dystrophy as 'cone-rod dystrophy.'


.0005 RETINITIS PIGMENTOSA 38

MERTK, 9-KB DEL
   RCV000030842

In affected members of 2 consanguineous Middle Eastern families with retinal dystrophy (RP38; 613862), Mackay et al. (2010) identified homozygosity for an approximately 9-kb deletion, encompassing exon 8 as well as part of introns 7 and 8 of the MERTK gene, that was predicted to disrupt the reading frame and result in a premature stop codon in exon 9. The deletion was present in heterozygosity in unaffected family members, but was not found in 100 control DNA samples from Saudi Arabia. Haplotype analysis showed that the 2 families shared a region of at least 500 kb based on 2 markers, D2S160 and D2S1896.


.0006 RETINITIS PIGMENTOSA 38

MERTK, IVS1, G-A, +1
  
RCV000030843

For discussion of the splice site mutation in the MERTK gene (61+1G-A) that was found in compound heterozygous state in a patient with childhood-onset rod-cone dystrophy (RP38; 613862) and early macular atrophy by Mackay et al. (2010), see 604705.0003.


.0007 RETINITIS PIGMENTOSA 38

MERTK, 91-KB DEL
   RCV000030844

In 6 patients with retinitis pigmentosa (RP38; 613862) from 4 consanguineous families from the Faroe Islands, Ostergaard et al. (2011) identified homozygosity for an approximately 91-kb deletion in the MERTK gene, encompassing exons 1 to 7. In 1 of the families, 1 affected member was heterozygous for the deletion, and sequencing of MERTK did not reveal another mutation; the authors suggested that RP might be caused by mutations in a different gene in that patient. The 91-kb deletion was present in heterozygosity in 3 of 94 anonymous Faroese controls, corresponding to a carrier frequency of approximately 3%. Ostergaard et al. (2011) concluded that this deletion represents a founder mutation in the Faroe Islands, responsible for about 30% of RP in that population.


.0008 RETINITIS PIGMENTOSA 38

MERTK, ARG775TER
  
RCV000030845...

In 3 affected sibs from a consanguineous Moroccan family with rod-cone dystrophy (RP38; 613862), Ksantini et al. (2012) identified homozygosity for a 2323C-T transition in exon 17 of the MERTK gene, resulting in an arg775-to-ter (R775X) substitution in the tyrosine kinase domain. The mutation segregated with disease in the family and was not found in 100 control chromosomes.


REFERENCES

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  4. D'Cruz, P. M., Yasumura, D., Weir, J., Matthes, M. T., Abderrahim, H., LaVail, M. M., Vollrath, D. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Molec. Genet. 9: 645-651, 2000. [PubMed: 10699188, related citations] [Full Text]

  5. Ebermann, I., Walger, M., Scholl, H. P. N., Issa, P. C., Luke, C., Nurnberg, G., Lang-Roth, R., Becker, C., Nurnberg, P., Bolz, H. J. Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum. Mutat. 28: 571-577, 2007. [PubMed: 17301963, related citations] [Full Text]

  6. Fourgeaud, L., Traves, P. G., Tufail, Y., Leal-Bailey, H., Lew, E. D., Burrola, P. G., Callaway, P., Zagorska, A., Rothlin, C. V., Nimmerjahn, A., Lemke, G. TAM receptors regulate multiple features of microglial physiology. Nature 532: 240-244, 2016. [PubMed: 27049947, images, related citations] [Full Text]

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  8. Graham, D. K., Dawson, T. L., Mullaney, D. L., Snodgrass, H. R., Earp, H. S. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ. 5: 647-657, 1994. Note: Erratum: Cell Growth Differ. 5: 1022 only, 1994. [PubMed: 8086340, related citations]

  9. Khan, T. N., Wong, E. B., Soni, C., Rahman, Z. S. M. Prolonged apoptotic cell accumulation in germinal centers of Mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production. J. Immun. 190: 1433-1446, 2013. [PubMed: 23319738, images, related citations] [Full Text]

  10. Ksantini, M., Lafont, E., Bocquet, B., Meunier, I., Hamel, C. P. Homozygous mutation in MERTK causes severe autosomal recessive retinitis pigmentosa. Europ. J. Ophthal. 22: 647-653, 2012. [PubMed: 22180149, related citations] [Full Text]

  11. Lu, Q., Gore, M., Zhang, Q., Camenisch, T., Boast, S., Casagranda, F., Lai, C., Skinner, M. K., Klein, R., Matsushima, G. K., Earp, H. S., Goff, S. P., Lemke, G. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398: 723-728, 1999. [PubMed: 10227296, related citations] [Full Text]

  12. Lu, Q., Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293: 306-311, 2001. [PubMed: 11452127, related citations] [Full Text]

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  14. Ostergaard, E., Duno, M., Batbayli, M., Vilhelmsen, K., Rosenberg, T. A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases. Molec. Vision 17: 1485-1492, 2011. [PubMed: 21677792, images, related citations]

  15. Paolino, M., Choidas, A., Wallner, S., Pranjic, B. Uribesalgo, I., Loeser, S., Jamieson, A. M., Langdon, W. Y., Ikeda, F., Fededa, J. P., Cronin, S. J., Nitsch, R., and 12 others. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507: 508-512, 2014. [PubMed: 24553136, related citations] [Full Text]

  16. Png, K. J., Halberg, N., Yoshida, M., Tavazoie, S. F. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 481: 190-194, 2012.

  17. Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B. A., Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131: 1124-1136, 2007. [PubMed: 18083102, related citations] [Full Text]

  18. Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., Matsushima, G. K. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411: 207-211, 2001. [PubMed: 11346799, related citations] [Full Text]

  19. Thompson, D. A., McHenry, C. L., Li, Y., Richards, J. E., Othman, M. I., Schwinger, E., Vollrath, D., Jacobson, S. G., Gal, A. Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. Am. J. Hum. Genet. 70: 224-229, 2002. [PubMed: 11727200, images, related citations] [Full Text]

  20. Vollrath, D., Feng, W., Duncan, J. L., Yasumura, D., D'Cruz, P. M., Chappelow, A., Matthes, M. T., Kay, M. A., LaVail, M. M. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc. Nat. Acad. Sci. 98: 12584-12589, 2001. [PubMed: 11592982, images, related citations] [Full Text]

  21. Weier, H.-U. G., Fung, J., Lersch, R. A. Assignment of protooncogene MERTK (a.k.a. c-mer) to human chromosome 2q14.1 by in situ hybridization. Cytogenet. Cell Genet. 84: 91-92, 1999. [PubMed: 10343112, related citations] [Full Text]

  22. Zhang, Y., Rauch, U., Perez, M.-T. R. Accumulation of neurocan, a brain chondroitin sulfate proteoglycan, in association with the retinal vasculature in RCS rats. Invest. Ophthal. Vis. Sci. 44: 1252-1261, 2003. [PubMed: 12601056, related citations] [Full Text]


Ada Hamosh - updated : 09/29/2016
Ada Hamosh - updated : 4/14/2014
Ada Hamosh - updated : 1/14/2014
Paul J. Converse - updated : 11/6/2013
Marla J. F. O'Neill - updated : 10/8/2012
Ada Hamosh - updated : 2/7/2012
Paul J. Converse - updated : 3/14/2008
Cassandra L. Kniffin - updated : 7/9/2007
Marla J. F. O'Neill - updated : 4/12/2005
Jane Kelly - updated : 3/3/2004
Victor A. McKusick - updated : 1/22/2002
Victor A. McKusick - updated : 1/11/2002
Paul J. Converse - updated : 8/8/2001
Ada Hamosh - updated : 5/8/2001
Victor A. McKusick - updated : 10/25/2000
George E. Tiller - updated : 4/14/2000
Creation Date:
Wilson H. Y. Lo : 3/20/2000
carol : 09/30/2016
alopez : 09/29/2016
mcolton : 02/11/2015
alopez : 4/14/2014
alopez : 1/30/2014
alopez : 1/14/2014
mgross : 11/12/2013
mcolton : 11/7/2013
mcolton : 11/6/2013
carol : 9/26/2013
carol : 10/16/2012
carol : 10/9/2012
terry : 10/8/2012
alopez : 2/13/2012
terry : 2/7/2012
alopez : 4/4/2011
mgross : 3/14/2008
carol : 11/30/2007
wwang : 7/12/2007
ckniffin : 7/9/2007
tkritzer : 4/12/2005
joanna : 3/17/2004
alopez : 3/3/2004
alopez : 4/3/2002
carol : 2/5/2002
mcapotos : 1/31/2002
terry : 1/22/2002
carol : 1/20/2002
mcapotos : 1/11/2002
mgross : 8/8/2001
cwells : 5/30/2001
alopez : 5/9/2001
terry : 5/8/2001
alopez : 10/31/2000
terry : 10/25/2000
alopez : 4/18/2000
terry : 4/14/2000
carol : 3/27/2000
carol : 3/27/2000

* 604705

MER TYROSINE KINASE PROTOONCOGENE; MERTK


HGNC Approved Gene Symbol: MERTK

Cytogenetic location: 2q13     Genomic coordinates (GRCh38): 2:111,898,607-112,029,561 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q13 Retinitis pigmentosa 38 613862 Autosomal recessive 3

TEXT

Cloning and Expression

By screening a human B-lymphoblastoid lambda-gt11 expression library with polyclonal antiphosphotyrosine antisera, Graham et al. (1994) obtained a cDNA clone encoding a novel tyrosine kinase, MERTK, which the authors designated c-mer. They subsequently obtained genomic clones from a human placenta genomic library. MERTK encodes a 984-amino acid protein with a calculated molecular mass of 109 kD. It shares 71% amino acid sequence identity with the chicken retroviral oncogene v-ryk. The protein has a putative transmembrane segment, a tyrosine kinase domain, several N-glycosylation sites, and tyrosine phosphorylation sites. MERTK shows similarity to AXL (109135), another tyrosine kinase, in that it contains 2 amino terminal immunoglobulin domains and 2 membrane proximal fibronectin type III domains in its extracellular region as well as the kinase signature sequence KWIAIES. MERTK is not expressed in normal B- and T-lymphocytes but, unlike AXL, is expressed in numerous neoplastic B- and T-cell lines. Transcripts for this novel receptor-like tyrosine kinase were detected in normal peripheral blood monocytes, bone marrow, and tissues of epithelial and reproductive origin. One alternatively spliced transcript, which contained an insert in the membrane proximal region, could encode for a truncated, soluble receptor.


Gene Function

Loss of function of the 3 TAM receptors, Tyro3 (600341), Axl, and Mer, results in profound dysregulation of the immune response in mice (see ANIMAL MODEL). By analyzing TAM function in the dendritic cell subset of mouse antigen-presenting cells, Rothlin et al. (2007) found that TAM inhibited inflammation through an essential stimulator of inflammation, Ifnar (107450), and its associated transcription factor, Stat1 (600555). Toll-like receptor (TLR; see 601194) induction of Ifnar-Stat1 signaling upregulated the TAM system, which, in turn, induced the cytokine and TLR suppressors Socs1 (603597) and Socs3 (604176). Rothlin et al. (2007) concluded that cytokine-dependent activation of TAM signaling diverts a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.

Png et al. (2012) demonstrated that endogenous miR126 (611767), a miRNA silenced in a variety of human cancers, non-cell-autonomously regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. It suppresses metastatic endothelial recruitment, metastatic angiogenesis, and metastatic colonization through coordinate targeting of IGFBP2 (146731), PITPNC1 (605134), and MERTK--novel proangiogenic genes and biomarkers of human metastasis. Insulin-like growth factor binding protein-2 (IGFBP2) secreted by metastatic cells recruits endothelia by modulating IGF1 (147440)-mediated activation of the IGF type-I receptor (147370) on endothelial cells, whereas MERTK receptor cleaved from metastatic cells promotes endothelial recruitment by competitively antagonizing the binding of its ligand GAS6 to endothelial MERTK receptors. Coinjection of endothelial cells with breast cancer cells non-cell-autonomously rescues their miR126-induced metastatic defect, revealing a novel and important role for endothelial interactions in metastatic initiation. Through loss-of-function and epistasis experiments, Png et al. (2012) delineated a miRNA regulator network's individual components as novel and cell-extrinsic regulators of endothelial recruitment, angiogenesis, and metastatic colonization. The authors also identified the IGFBP2/IGF1/IGF1R and GAS6/MERTK signaling pathways as regulators of cancer-mediated endothelial recruitment.

Chung et al. (2013) reported a role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 (612453) and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways failed to refine their retinogeniculate connections normally and retained excess functional synapses. Finally, Chung et al. (2013) showed that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. Chung et al. (2013) concluded that their studies revealed a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, and identified MEGF10 and MERTK as critical proteins in the synapse remodeling underlying neural circuit refinement.

Paolino et al. (2014) demonstrated that genetic deletion of the E3 ubiquitin ligase CBLB (604491) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumors. The TAM tyrosine kinase receptors TYRO3, AXL, and MERTK were identified as ubiquitylation substrates for CBLB. Treatment of wildtype NK cells with a small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing antimetastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. Paolino et al. (2014) further reported that the anticoagulant warfarin exerts antimetastatic activity in mice via Cblb/TAM receptors in NK cells, providing a molecular explanation for the effect of warfarin to reduce tumor metastases in rodent models. Paolino et al. (2014) concluded that this novel TAM/CBLB inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

Fourgeaud et al. (2016) demonstrated that the TAM receptor tyrosine kinases Mer and Axl regulate the microglial functions of damage sensing and routine noninflammatory clearance of dead brain cells. Fourgeaud et al. (2016) found that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the central nervous system (CNS), and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 (600441) and protein S (176880). Using live 2-photon imaging, the authors demonstrated that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Fourgeaud et al. (2016) also showed that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson disease (168600). Fourgeaud et al. (2016) concluded that these results established TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.


Mapping

By fluorescence in situ hybridization, Weier et al. (1999) mapped the MERTK gene to chromosome 2q14.1.


Molecular Genetics

Gal et al. (2000) screened the MERTK gene, the human ortholog of the RCS rat retinal dystrophy gene, in 328 DNA samples from individuals with various retinal dystrophies and found 3 mutations in 3 unrelated individuals with retinitis pigmentosa (604705.0001-604705.0003). This finding was the first conclusive evidence implicating the retinal pigment epithelium (RPE) phagocytosis pathway in human retinal disease. They examined each of the 19 coding exons of MERTK and adjacent splice sites for evidence of mutation by SSCP or direct sequencing.

Thompson et al. (2002) found paternal isodisomy for chromosome 2 in a woman with retinitis pigmentosa and an apparently homozygous MERTK mutation, IVS10-2A-G (604705.0002), that was present in heterozygous form in her unaffected father but was not present in her mother. Analysis of haplotypes indicated the absence of the maternal allele for all informative markers on chromosome 2. This provided the first evidence that chromosome 2 carries no paternally imprinted genes that have a major effect on phenotype.

In 5 sibs from a consanguineous Moroccan family with retinal dystrophy, Ebermann et al. (2007) identified homozygosity for a splice site mutation in the MERTK gene (604705.0004).

In affected members of 2 consanguineous Middle Eastern families with retinal dystrophy, Mackay et al. (2010) identified homozygosity for a deletion involving exon 8 of the MERTK gene (604705.0005). In a Caucasian man with childhood-onset rod-cone dystrophy, the authors identified compound heterozygosity for the known MERTK nonsense mutation R651X (604705.0003) and a splice site mutation (604705.0006).

In 7 of 21 cases of RP in the Faroe Islands, Ostergaard et al. (2011) identified a 91-bp deletion in the MERTK gene (604705.0007).

In a consanguineous Moroccan family with the rod-cone dystrophy type of RP, Ksantini et al. (2012) identified homozygosity for a nonsense mutation in the tyrosine kinase domain of MERTK (R775X; 604705.0008).


Animal Model

The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the retinal pigment epithelium (RPE) fails to phagocytose shed outer segments, and photoreceptor cells subsequently die. D'Cruz et al. (2000) used a positional cloning approach to localize the rdy (retinal dystrophy) locus of the RCS rat to within a 0.3-cM interval on rat chromosome 3. The authors discovered a small deletion of RCS DNA that disrupted Mertk. The deletion resulted in a shortened transcript with a termination signal 20 codons after the AUG. The authors concluded that Mertk is probably the gene for rdy.

Camenisch et al. (1999) generated a functional knockout mouse with a truncation of the Mer cytoplasmic tail (Mer-kd). Scott et al. (2001) showed these mice to have macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimeric mice reconstituted with bone marrow from wildtype animals. Primary macrophages isolated from Mer-kd mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor (see 605484)-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in Mer-kd mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. Scott et al. (2001) concluded that this may have implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (152700). Lu et al. (1999) generated mice deficient in Mertk, Axl, and Tyro3. Triply deficient male mice were infertile due to degenerative spermatogenesis. In addition, triply deficient mice were blind and had neurologic abnormalities and splenomegaly owing to increased numbers of apoptotic cells. Scott et al. (2001) suggested that the removal of apoptotic cells mediated partly by the cytoplasmic signaling domain of Mer may be critical to the maintenance of tissue homeostasis and the prevention of autoimmunity.

Regulation of lymphocyte numbers is mediated by cytokines signaling through receptors coupled to cytoplasmic protein-tyrosine kinases. Lu and Lemke (2001) generated mice deficient in Mertk, Axl, and Tyro3. Like their ligands, GAS6 (600441) and PROS1 (176880), these receptors are widely expressed in monocytes and macrophages but not in B or T lymphocytes. Although the peripheral lymphoid organs of mutant mice were indistinguishable from those of wildtype mice at birth, by 4 weeks of age spleens and lymph nodes grew at elevated rates. This was primarily due to the hyperproliferation of constitutively activated B and T cells, particularly CD4-positive T cells, with ectopic colonies in every adult organ examined. All triple mutants developed autoimmunity with symptoms histologically similar to human rheumatoid arthritis (180300), pemphigus vulgaris (169610), and systemic lupus erythematosus, and were characterized by antibodies against normal cellular antigens, including phospholipids and double-stranded DNA. Females were particularly prone to thromboses and recurrent fetal loss. Flow cytometric analysis demonstrated that wildtype B and T cells underwent multiple rounds of cell division after injection into mutant mice and that their antigen-presenting cells expressed elevated levels of activation markers. Lu and Lemke (2001) proposed that the cells that initiate lymphoproliferation and autoimmunity in the Tyro3 family mutants were the macrophages and dendritic cells that normally express the 3 receptor genes.

Vollrath et al. (2001) sought to determine whether gene transfer of MERTK to an RCS rat retina would result in correction of the phagocytosis defect in the retinal pigment epithelium and preservation of photoreceptors. They used subretinal injection of a recombinant replication-deficient adenovirus encoding rat MERTK to deliver the gene to the eyes of young RCS rats. Electrophysiologic, histologic, and ultrastructural assessment indicated a correction of the retinal dystrophy phenotype. Results provided definitive evidence that mutation of MERTK underlies the RCS retinal dystrophy phenotype. Vollrath et al. (2001) stated that this was the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE.

Zhang et al. (2003) examined the retinal distribution of the chondroitin sulfate proteoglycan neurocan (600826) in RCS rats. Neurocan accumulation in association with the retinal vasculature did not correlate with photoreceptor cell loss, because similar deposits were not observed in the retinas of rhodopsin mutant rats. In RCS rats, however, neurocan immunostaining was seen in association with retinal vessels from postnatal day 15 onward. The authors hypothesized that with time, the accumulated perivascular neurocan might, via interaction with other matrix molecules, modulate at least some of the vascular alterations observed in the RCS rat model.

Angelillo-Scherrer et al. (2005) generated mice lacking 1 of the 3 Gas6 receptors: Tyro3, Axl, or Mertk. Loss of any 1 of the Gas6 receptors or delivery of a soluble extracellular domain of Axl that traps Gas6 protected the mice against life-threatening thrombosis. Loss of a Gas6 receptor did not prevent initial platelet aggregation but impaired subsequent stabilization of platelet aggregates, at least in part by reducing outside-in signaling and platelet granule secretion. Gas6, through its receptors, activated PI3K and Akt (see 164730) and stimulated tyrosine phosphorylation of the beta-3 integrin (173470), thereby amplifying outside-in signaling via alpha-IIb (607759)-beta-3.

Khan et al. (2013) found that Mer -/- mice showed accumulation of apoptotic cells (ACs) primarily in germinal centers (GCs), where Mer is normally expressed on macrophages, but not on B or T cells. AC accumulation in GCs of Mer -/- mice led to augmented antibody-forming cell and IgG2 responses persisting for at least 80 days. The enhanced responses were due to increased activation and proliferation of B cells and Cd4 (186940)-positive T-helper (Th) cells. Secondary total IgG and IgG2 responses were also increased in Mer -/- mice. Consistent with the elevated levels of IgG2 antibodies, Mer -/- mice also had an increased percentage of Ifng (147570)-producing Cd4 cells and increased levels of Th1 (i.e., IL2, 147680, and Ifng) and proinflammatory (i.e., Tnf, 191160, and IL6, 147620) cytokines. Khan et al. (2013) concluded that Mer deficiency induces prolonged accumulation of ACs in GCs, resulting in dysregulation of GC B-cell and Cd4-positive Th-cell responses and Th1 cytokine production, leading to alteration of B-cell tolerance and development of autoantibodies.


ALLELIC VARIANTS 8 Selected Examples):

.0001   RETINITIS PIGMENTOSA 38

MERTK, 5-BP DEL, NT2070
SNP: rs1573638426, ClinVar: RCV001001159, RCV001268553

In a sample from a 45-year-old man with retinitis pigmentosa (RP38; 613862) who was the offspring of a consanguineous union, Gal et al. (2000) found an apparently homozygous 5-bp deletion in exon 15 (2070delAGGAC) of the MERTK gene. He had onset of night blindness and poor vision in early childhood and at the time of study had only a small central island of remaining vision. Two children were heterozygous. The mutation resulted in a frameshift after codon 690, predicting inclusion of 41 MERTK-unrelated amino acid residues before premature termination. This predicted mutant protein would lack nearly one-third of the wildtype residues, including most of the conserved tyrosine kinase domain.


.0002   RETINITIS PIGMENTOSA 38

MERTK, IVS10AS, A-G, -2
SNP: rs730880273, gnomAD: rs730880273, ClinVar: RCV000005732, RCV001071534, RCV001073657

In a sample from a 34-year-old woman with retinitis pigmentosa (RP38; 613862) whose unaffected parents were not known to be related, Gal et al. (2000) found an apparently homozygous A-to-G transition in the intron 10 splice acceptor site of the MERTK gene. She had onset of night blindness and poor vision in early childhood and at the time of study had only a small central island of remaining vision. The splice mutation, which ablated a consensus nucleotide (-2) of the acceptor site, was predicted to result in aberrant splicing of the MERTK transcript. The proband's father, but not her mother, was heterozygous for the splice site change. Further studies demonstrated that the proband was disomic for the paternal homolog (Thompson et al., 2002).


.0003   RETINITIS PIGMENTOSA 38

MERTK, ARG651TER
SNP: rs119489105, gnomAD: rs119489105, ClinVar: RCV000005733, RCV001054980, RCV001257901, RCV001723542

In a sample from a 21-year-old woman with retinitis pigmentosa (RP38; 613862) who had had poor vision as a child, Gal et al. (2000) found a heterozygous premature termination codon (arg651 to ter; R651X) in the MERTK gene. At age 12, she had complaints of night blindness. A second mutation was not found in this individual by direct sequencing of exons 1 through 19 of the MERTK gene.

In a 22-year-old Caucasian man with childhood-onset rod-cone dystrophy and early macular atrophy, Mackay et al. (2010) identified compound heterozygosity for the R651X mutation in the MERTK gene, and a G-A transition in intron 1 (61+1G-A; 604705.0006), predicted to disrupt the donor splice site. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 100 ethnically matched controls.


.0004   RETINITIS PIGMENTOSA 38

MERTK, IVS16DS, G-T, +1
SNP: rs371956016, gnomAD: rs371956016, ClinVar: RCV000005734, RCV000624145, RCV001073654, RCV001208965, RCV001257903, RCV003324483

In 5 sibs from a consanguineous Moroccan family with retinal dystrophy (RP38; 613862), Ebermann et al. (2007) identified a homozygous G-to-T transversion in intron 16 (2189+1G-T), resulting in the skipping of exon 16 and truncation of the protein to 696 residues. Ebermann et al. (2007) classified the retinal dystrophy as 'cone-rod dystrophy.'


.0005   RETINITIS PIGMENTOSA 38

MERTK, 9-KB DEL
ClinVar: RCV000030842

In affected members of 2 consanguineous Middle Eastern families with retinal dystrophy (RP38; 613862), Mackay et al. (2010) identified homozygosity for an approximately 9-kb deletion, encompassing exon 8 as well as part of introns 7 and 8 of the MERTK gene, that was predicted to disrupt the reading frame and result in a premature stop codon in exon 9. The deletion was present in heterozygosity in unaffected family members, but was not found in 100 control DNA samples from Saudi Arabia. Haplotype analysis showed that the 2 families shared a region of at least 500 kb based on 2 markers, D2S160 and D2S1896.


.0006   RETINITIS PIGMENTOSA 38

MERTK, IVS1, G-A, +1
SNP: rs1573554264, ClinVar: RCV000030843

For discussion of the splice site mutation in the MERTK gene (61+1G-A) that was found in compound heterozygous state in a patient with childhood-onset rod-cone dystrophy (RP38; 613862) and early macular atrophy by Mackay et al. (2010), see 604705.0003.


.0007   RETINITIS PIGMENTOSA 38

MERTK, 91-KB DEL
ClinVar: RCV000030844

In 6 patients with retinitis pigmentosa (RP38; 613862) from 4 consanguineous families from the Faroe Islands, Ostergaard et al. (2011) identified homozygosity for an approximately 91-kb deletion in the MERTK gene, encompassing exons 1 to 7. In 1 of the families, 1 affected member was heterozygous for the deletion, and sequencing of MERTK did not reveal another mutation; the authors suggested that RP might be caused by mutations in a different gene in that patient. The 91-kb deletion was present in heterozygosity in 3 of 94 anonymous Faroese controls, corresponding to a carrier frequency of approximately 3%. Ostergaard et al. (2011) concluded that this deletion represents a founder mutation in the Faroe Islands, responsible for about 30% of RP in that population.


.0008   RETINITIS PIGMENTOSA 38

MERTK, ARG775TER
SNP: rs387907314, gnomAD: rs387907314, ClinVar: RCV000030845, RCV001257797, RCV001852614

In 3 affected sibs from a consanguineous Moroccan family with rod-cone dystrophy (RP38; 613862), Ksantini et al. (2012) identified homozygosity for a 2323C-T transition in exon 17 of the MERTK gene, resulting in an arg775-to-ter (R775X) substitution in the tyrosine kinase domain. The mutation segregated with disease in the family and was not found in 100 control chromosomes.


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Contributors:
Ada Hamosh - updated : 09/29/2016
Ada Hamosh - updated : 4/14/2014
Ada Hamosh - updated : 1/14/2014
Paul J. Converse - updated : 11/6/2013
Marla J. F. O'Neill - updated : 10/8/2012
Ada Hamosh - updated : 2/7/2012
Paul J. Converse - updated : 3/14/2008
Cassandra L. Kniffin - updated : 7/9/2007
Marla J. F. O'Neill - updated : 4/12/2005
Jane Kelly - updated : 3/3/2004
Victor A. McKusick - updated : 1/22/2002
Victor A. McKusick - updated : 1/11/2002
Paul J. Converse - updated : 8/8/2001
Ada Hamosh - updated : 5/8/2001
Victor A. McKusick - updated : 10/25/2000
George E. Tiller - updated : 4/14/2000

Creation Date:
Wilson H. Y. Lo : 3/20/2000

Edit History:
carol : 09/30/2016
alopez : 09/29/2016
mcolton : 02/11/2015
alopez : 4/14/2014
alopez : 1/30/2014
alopez : 1/14/2014
mgross : 11/12/2013
mcolton : 11/7/2013
mcolton : 11/6/2013
carol : 9/26/2013
carol : 10/16/2012
carol : 10/9/2012
terry : 10/8/2012
alopez : 2/13/2012
terry : 2/7/2012
alopez : 4/4/2011
mgross : 3/14/2008
carol : 11/30/2007
wwang : 7/12/2007
ckniffin : 7/9/2007
tkritzer : 4/12/2005
joanna : 3/17/2004
alopez : 3/3/2004
alopez : 4/3/2002
carol : 2/5/2002
mcapotos : 1/31/2002
terry : 1/22/2002
carol : 1/20/2002
mcapotos : 1/11/2002
mgross : 8/8/2001
cwells : 5/30/2001
alopez : 5/9/2001
terry : 5/8/2001
alopez : 10/31/2000
terry : 10/25/2000
alopez : 4/18/2000
terry : 4/14/2000
carol : 3/27/2000
carol : 3/27/2000