RBCC Red Blood Cell Collection

MERTK (MER) [Confidence: low (only semi-automatic identification from reviews)]
Tyrosine-protein kinase Mer; 2.7.10.1 (Proto-oncogene c-Mer; Receptor tyrosine kinase MerTK; Flags: Precursor)

UniProt Q12866
ID MERTK_HUMAN Reviewed; 999 AA.
AC Q12866; Q9HBB4;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-NOV-2007, sequence version 2.
DT 22-JAN-2014, entry version 158.
DE RecName: Full=Tyrosine-protein kinase Mer;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene c-Mer;
DE AltName: Full=Receptor tyrosine kinase MerTK;
DE Flags: Precursor;
GN Name=MERTK; Synonyms=MER;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASN-118.
RC TISSUE=Peripheral blood leukocyte;
RX PubMed=8086340;
RA Graham D.K., Dawson T.L., Mullaney D.L., Snodgrass H.R., Earp H.S.;
RT "Cloning and mRNA expression analysis of a novel human protooncogene,
RT c-mer.";
RL Cell Growth Differ. 5:647-657(1994).
RN [2]
RP ERRATUM.
RA Graham D.K., Dawson T.L., Mullaney D.L., Snodgrass H.R., Earp H.S.;
RL Cell Growth Differ. 5:1022-1022(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 22-999, VARIANTS RP38 LYS-540;
RP CYS-661 AND THR-871, AND VARIANTS SER-20; ASN-118; THR-282; HIS-293;
RP LYS-466; SER-498; VAL-518 AND VAL-871.
RX PubMed=11062461; DOI=10.1038/81555;
RA Gal A., Li Y., Thompson D.A., Weir J., Orth U., Jacobson S.G.,
RA Apfelstedt-Sylla E., Vollrath D.;
RT "Mutations in MERTK, the human orthologue of the RCS rat retinal
RT dystrophy gene, cause retinitis pigmentosa.";
RL Nat. Genet. 26:270-271(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP AUTOPHOSPHORYLATION AT TYR-749; TYR-753 AND TYR-754.
RX PubMed=8702477; DOI=10.1074/jbc.271.31.18355;
RA Ling L., Templeton D., Kung H.J.;
RT "Identification of the major autophosphorylation sites of Nyk/Mer, an
RT NCAM-related receptor tyrosine kinase.";
RL J. Biol. Chem. 271:18355-18362(1996).
RN [6]
RP INTERACTION WITH GAS6.
RX PubMed=9160883; DOI=10.1038/sj.onc.1201039;
RA Chen J., Carey K., Godowski P.J.;
RT "Identification of Gas6 as a ligand for Mer, a neural cell adhesion
RT molecule related receptor tyrosine kinase implicated in cellular
RT transformation.";
RL Oncogene 14:2033-2039(1997).
RN [7]
RP INTERACTION WITH VAV1.
RX PubMed=12920122; DOI=10.1074/jbc.M305817200;
RA Mahajan N.P., Earp H.S.;
RT "An SH2 domain-dependent, phosphotyrosine-independent interaction
RT between Vav1 and the Mer receptor tyrosine kinase: a mechanism for
RT localizing guanine nucleotide-exchange factor action.";
RL J. Biol. Chem. 278:42596-42603(2003).
RN [8]
RP INTERACTION WITH TNK2.
RX PubMed=16288044; DOI=10.1158/0008-5472.CAN-05-1127;
RA Mahajan N.P., Whang Y.E., Mohler J.L., Earp H.S.;
RT "Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role
RT of Ack1 in polyubiquitination of tumor suppressor Wwox.";
RL Cancer Res. 65:10514-10523(2005).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-442, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [10]
RP REVIEW ON FUNCTION.
RX PubMed=16737840; DOI=10.1016/j.cytogfr.2006.04.004;
RA Hafizi S., Dahlback B.;
RT "Signalling and functional diversity within the Axl subfamily of
RT receptor tyrosine kinases.";
RL Cytokine Growth Factor Rev. 17:295-304(2006).
RN [11]
RP FUNCTION AS CELL ENTRY FACTOR IN FILOVIRUS INFECTION.
RX PubMed=17005688; DOI=10.1128/JVI.01157-06;
RA Shimojima M., Takada A., Ebihara H., Neumann G., Fujioka K.,
RA Irimura T., Jones S., Feldmann H., Kawaoka Y.;
RT "Tyro3 family-mediated cell entry of Ebola and Marburg viruses.";
RL J. Virol. 80:10109-10116(2006).
RN [12]
RP REVIEW ON FUNCTION.
RX PubMed=18421305; DOI=10.1038/nri2303;
RA Lemke G., Rothlin C.V.;
RT "Immunobiology of the TAM receptors.";
RL Nat. Rev. Immunol. 8:327-336(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-543 AND SER-935, AND
RP MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP INTERACTION WITH LGALS3.
RX PubMed=21792939; DOI=10.1002/jcp.22955;
RA Caberoy N.B., Alvarado G., Bigcas J.L., Li W.;
RT "Galectin-3 is a new MerTK-specific eat-me signal.";
RL J. Cell. Physiol. 227:401-407(2012).
RN [15]
RP STRUCTURE BY NMR OF 366-483.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structures of the FN3 domain of human proto-oncogene
RT tyrosine-protein kinase MER precursor.";
RL Submitted (DEC-2006) to the PDB data bank.
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-20; ASN-118; MET-185; THR-282;
RP LYS-289; HIS-293; GLY-446; LEU-452; LYS-466; SER-498; VAL-518;
RP GLU-662; SER-708; GLN-823; TRP-865 AND ILE-870.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [17]
RP VARIANTS VAL-214 AND LEU-958.
RX PubMed=21602930; DOI=10.1371/journal.pone.0019458;
RA Li L., Xiao X., Li S., Jia X., Wang P., Guo X., Jiao X., Zhang Q.,
RA Hejtmancik J.F.;
RT "Detection of variants in 15 genes in 87 unrelated Chinese patients
RT with Leber congenital amaurosis.";
RL PLoS ONE 6:E19458-E19458(2011).
CC -!- FUNCTION: Receptor tyrosine kinase that transduces signals from
CC the extracellular matrix into the cytoplasm by binding to several
CC ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many
CC physiological processes including cell survival, migration,
CC differentiation, and phagocytosis of apoptotic cells
CC (efferocytosis). Ligand binding at the cell surface induces
CC autophosphorylation of MERTK on its intracellular domain that
CC provides docking sites for downstream signaling molecules.
CC Following activation by ligand, interacts with GRB2 or PLCG2 and
CC induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK
CC signaling plays a role in various processes such as macrophage
CC clearance of apoptotic cells, platelet aggregation, cytoskeleton
CC reorganization and engulfment. Functions in the retinal pigment
CC epithelium (RPE) as a regulator of rod outer segments fragments
CC phagocytosis. Plays also an important role in inhibition of Toll-
CC like receptors (TLRs)-mediated innate immune response by
CC activating STAT1, which selectively induces production of
CC suppressors of cytokine signaling SOCS1 and SOCS3.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- SUBUNIT: Interacts (upon activation) with TNK2; stimulates TNK2
CC autophosphorylation. Interacts (via N-terminus) with extracellular
CC ligands LGALS3, TUB, TULP1 and GAS6 (By similarity). Interacts
CC with VAV1 in a phosphotyrosine-independent manner.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein (By similarity).
CC -!- TISSUE SPECIFICITY: Not expressed in normal B- and T-lymphocytes
CC but is expressed in numerous neoplastic B- and T-cell lines.
CC Highly expressed in testis, ovary, prostate, lung, and kidney,
CC with lower expression in spleen, small intestine, colon, and
CC liver.
CC -!- PTM: Autophosphorylated on Tyr-749, Tyr-753 and Tyr-754 in the
CC activation loop allowing full activity. Autophosphorylated on Tyr-
CC 872 leading to recruitment of downstream partners of the signaling
CC cascade such as PLCG2 (By similarity).
CC -!- DISEASE: Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal
CC dystrophy belonging to the group of pigmentary retinopathies.
CC Retinitis pigmentosa is characterized by retinal pigment deposits
CC visible on fundus examination and primary loss of rod
CC photoreceptor cells followed by secondary loss of cone
CC photoreceptors. Patients typically have night vision blindness and
CC loss of midperipheral visual field. As their condition progresses,
CC they lose their far peripheral visual field and eventually central
CC vision as well. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. AXL/UFO subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org//Genes/MERTKID41339ch2q13.html";
CC -!- WEB RESOURCE: Name=Mutations of the MERTK gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="http://www.retina-international.org/files/sci-news/mertkmut.htm";
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DR EMBL; U08023; AAB60430.1; -; mRNA.
DR EMBL; AH010001; AAG33129.1; -; Genomic_DNA.
DR EMBL; AC093675; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104651; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; I38547; I38547.
DR RefSeq; NP_006334.2; NM_006343.2.
DR UniGene; Hs.306178; -.
DR PDB; 2DBJ; NMR; -; A=373-483.
DR PDB; 2P0C; X-ray; 2.40 A; A/B=570-864.
DR PDB; 3BPR; X-ray; 2.80 A; A/B/C/D=574-864.
DR PDB; 3BRB; X-ray; 1.90 A; A/B=570-864.
DR PDB; 3TCP; X-ray; 2.69 A; A/B=570-864.
DR PDBsum; 2DBJ; -.
DR PDBsum; 2P0C; -.
DR PDBsum; 3BPR; -.
DR PDBsum; 3BRB; -.
DR PDBsum; 3TCP; -.
DR ProteinModelPortal; Q12866; -.
DR SMR; Q12866; 128-280, 286-492, 575-900.
DR IntAct; Q12866; 3.
DR STRING; 9606.ENSP00000295408; -.
DR BindingDB; Q12866; -.
DR ChEMBL; CHEMBL5331; -.
DR GuidetoPHARMACOLOGY; 1837; -.
DR MEROPS; I43.001; -.
DR PhosphoSite; Q12866; -.
DR DMDM; 160332297; -.
DR PaxDb; Q12866; -.
DR PRIDE; Q12866; -.
DR Ensembl; ENST00000295408; ENSP00000295408; ENSG00000153208.
DR Ensembl; ENST00000421804; ENSP00000389152; ENSG00000153208.
DR GeneID; 10461; -.
DR KEGG; hsa:10461; -.
DR UCSC; uc002thk.1; human.
DR CTD; 10461; -.
DR GeneCards; GC02P112656; -.
DR H-InvDB; HIX0002374; -.
DR HGNC; HGNC:7027; MERTK.
DR HPA; HPA036196; -.
DR MIM; 604705; gene.
DR MIM; 613862; phenotype.
DR neXtProt; NX_Q12866; -.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA30759; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000231685; -.
DR HOVERGEN; HBG006346; -.
DR InParanoid; Q12866; -.
DR KO; K05117; -.
DR OMA; NEIGWSA; -.
DR OrthoDB; EOG77DJ5C; -.
DR PhylomeDB; Q12866; -.
DR BRENDA; 2.7.10.1; 2681.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; Q12866; -.
DR ChiTaRS; MERTK; human.
DR EvolutionaryTrace; Q12866; -.
DR GeneWiki; MERTK; -.
DR GenomeRNAi; 10461; -.
DR NextBio; 39667; -.
DR PRO; PR:Q12866; -.
DR ArrayExpress; Q12866; -.
DR Bgee; Q12866; -.
DR CleanEx; HS_MERTK; -.
DR Genevestigator; Q12866; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0001750; C:photoreceptor outer segment; IEA:Ensembl.
DR GO; GO:0016028; C:rhabdomere; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; TAS:ProtInc.
DR GO; GO:0043277; P:apoptotic cell clearance; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0001779; P:natural killer cell differentiation; IEA:Ensembl.
DR GO; GO:0051250; P:negative regulation of lymphocyte activation; IEA:Ensembl.
DR GO; GO:0006909; P:phagocytosis; IMP:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; IEA:Ensembl.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IDA:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR GO; GO:0032940; P:secretion by cell; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IEA:Ensembl.
DR GO; GO:0060068; P:vagina development; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 4.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00409; IG; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS50835; IG_LIKE; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Complete proteome; Disease mutation;
KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Proto-oncogene;
KW Receptor; Reference proteome; Repeat; Retinitis pigmentosa; Signal;
KW Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase.
FT SIGNAL 1 20 Potential.
FT CHAIN 21 999 Tyrosine-protein kinase Mer.
FT /FTId=PRO_0000024443.
FT TOPO_DOM 21 505 Extracellular (Potential).
FT TRANSMEM 506 526 Helical; (Potential).
FT TOPO_DOM 527 999 Cytoplasmic (Potential).
FT DOMAIN 81 186 Ig-like C2-type 1.
FT DOMAIN 197 273 Ig-like C2-type 2.
FT DOMAIN 286 381 Fibronectin type-III 1.
FT DOMAIN 386 484 Fibronectin type-III 2.
FT DOMAIN 587 858 Protein kinase.
FT NP_BIND 593 601 ATP (By similarity).
FT ACT_SITE 723 723 Proton acceptor (By similarity).
FT BINDING 615 615 ATP (By similarity).
FT MOD_RES 543 543 Phosphoserine.
FT MOD_RES 749 749 Phosphotyrosine; by autocatalysis.
FT MOD_RES 753 753 Phosphotyrosine; by autocatalysis.
FT MOD_RES 754 754 Phosphotyrosine; by autocatalysis.
FT MOD_RES 872 872 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 935 935 Phosphoserine.
FT CARBOHYD 114 114 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 170 170 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 207 207 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 215 215 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 234 234 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 294 294 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 316 316 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 329 329 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 336 336 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 354 354 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 389 389 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 395 395 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 442 442 N-linked (GlcNAc...).
FT CARBOHYD 454 454 N-linked (GlcNAc...) (Potential).
FT DISULFID 115 175 By similarity.
FT DISULFID 218 262 By similarity.
FT VARIANT 20 20 R -> S (in dbSNP:rs35898499).
FT /FTId=VAR_021039.
FT VARIANT 118 118 S -> N (in dbSNP:rs13027171).
FT /FTId=VAR_021040.
FT VARIANT 185 185 V -> M (in dbSNP:rs56205303).
FT /FTId=VAR_041741.
FT VARIANT 214 214 F -> V (found in a patient with Leber
FT congenital amaurosis).
FT /FTId=VAR_067194.
FT VARIANT 282 282 A -> T (in dbSNP:rs7588635).
FT /FTId=VAR_021041.
FT VARIANT 289 289 E -> K.
FT /FTId=VAR_041742.
FT VARIANT 293 293 R -> H (in dbSNP:rs34072093).
FT /FTId=VAR_021042.
FT VARIANT 329 329 N -> S (in dbSNP:rs34943572).
FT /FTId=VAR_051698.
FT VARIANT 446 446 A -> G (in a renal clear cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041743.
FT VARIANT 452 452 V -> L (in dbSNP:rs34010621).
FT /FTId=VAR_041744.
FT VARIANT 466 466 R -> K (in dbSNP:rs7604639).
FT /FTId=VAR_021043.
FT VARIANT 498 498 N -> S (in dbSNP:rs35858762).
FT /FTId=VAR_021044.
FT VARIANT 518 518 I -> V (in dbSNP:rs2230515).
FT /FTId=VAR_021045.
FT VARIANT 540 540 E -> K (in RP38; dbSNP:rs113485015).
FT /FTId=VAR_021046.
FT VARIANT 661 661 S -> C (in RP38).
FT /FTId=VAR_021047.
FT VARIANT 662 662 Q -> E (in dbSNP:rs56209758).
FT /FTId=VAR_041745.
FT VARIANT 708 708 A -> S (in a head & Neck squamous cell
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041746.
FT VARIANT 823 823 E -> Q (in dbSNP:rs55924349).
FT /FTId=VAR_041747.
FT VARIANT 865 865 R -> W (in dbSNP:rs2230516).
FT /FTId=VAR_020285.
FT VARIANT 870 870 V -> I (in dbSNP:rs2230517).
FT /FTId=VAR_029237.
FT VARIANT 871 871 I -> T (in RP38).
FT /FTId=VAR_021048.
FT VARIANT 871 871 I -> V.
FT /FTId=VAR_021049.
FT VARIANT 958 958 P -> L (found in a patient with Leber
FT congenital amaurosis; dbSNP:rs201460398).
FT /FTId=VAR_067195.
FT CONFLICT 140 140 A -> G (in Ref. 1; AAB60430).
FT CONFLICT 143 143 A -> R (in Ref. 1; AAB60430).
FT CONFLICT 247 247 S -> G (in Ref. 1; AAB60430).
FT CONFLICT 274 274 K -> Q (in Ref. 1; AAB60430).
FT CONFLICT 328 328 S -> G (in Ref. 1; AAB60430).
FT CONFLICT 628 628 Q -> H (in Ref. 1; AAB60430).
FT CONFLICT 794 794 A -> R (in Ref. 1; AAB60430).
FT CONFLICT 888 888 S -> P (in Ref. 1; AAB60430).
FT STRAND 388 394
FT STRAND 396 406
FT STRAND 417 428
FT STRAND 431 441
FT STRAND 446 449
FT STRAND 453 459
FT STRAND 461 467
FT STRAND 476 479
FT TURN 577 580
FT HELIX 584 586
FT STRAND 587 594
FT STRAND 601 607
FT STRAND 613 620
FT HELIX 628 642
FT STRAND 654 657
FT STRAND 667 672
FT HELIX 679 685
FT STRAND 688 692
FT HELIX 697 715
FT TURN 716 718
FT HELIX 726 728
FT STRAND 729 731
FT STRAND 737 739
FT HELIX 764 766
FT HELIX 769 773
FT HELIX 779 794
FT HELIX 806 808
FT HELIX 809 814
FT HELIX 827 835
FT HELIX 841 843
FT HELIX 847 860
SQ SEQUENCE 999 AA; 110249 MW; 05BC339F05DFD355 CRC64;
MGPAPLPLLL GLFLPALWRR AITEAREEAK PYPLFPGPFP GSLQTDHTPL LSLPHASGYQ
PALMFSPTQP GRPHTGNVAI PQVTSVESKP LPPLAFKHTV GHIILSEHKG VKFNCSISVP
NIYQDTTISW WKDGKELLGA HHAITQFYPD DEVTAIIASF SITSVQRSDN GSYICKMKIN
NEEIVSDPIY IEVQGLPHFT KQPESMNVTR NTAFNLTCQA VGPPEPVNIF WVQNSSRVNE
QPEKSPSVLT VPGLTEMAVF SCEAHNDKGL TVSKGVQINI KAIPSPPTEV SIRNSTAHSI
LISWVPGFDG YSPFRNCSIQ VKEADPLSNG SVMIFNTSAL PHLYQIKQLQ ALANYSIGVS
CMNEIGWSAV SPWILASTTE GAPSVAPLNV TVFLNESSDN VDIRWMKPPT KQQDGELVGY
RISHVWQSAG ISKELLEEVG QNGSRARISV QVHNATCTVR IAAVTRGGVG PFSDPVKIFI
PAHGWVDYAP SSTPAPGNAD PVLIIFGCFC GFILIGLILY ISLAIRKRVQ ETKFGNAFTE
EDSELVVNYI AKKSFCRRAI ELTLHSLGVS EELQNKLEDV VIDRNLLILG KILGEGEFGS
VMEGNLKQED GTSLKVAVKT MKLDNSSQRE IEEFLSEAAC MKDFSHPNVI RLLGVCIEMS
SQGIPKPMVI LPFMKYGDLH TYLLYSRLET GPKHIPLQTL LKFMVDIALG MEYLSNRNFL
HRDLAARNCM LRDDMTVCVA DFGLSKKIYS GDYYRQGRIA KMPVKWIAIE SLADRVYTSK
SDVWAFGVTM WEIATRGMTP YPGVQNHEMY DYLLHGHRLK QPEDCLDELY EIMYSCWRTD
PLDRPTFSVL RLQLEKLLES LPDVRNQADV IYVNTQLLES SEGLAQGSTL APLDLNIDPD
SIIASCTPRA AISVVTAEVH DSKPHEGRYI LNGGSEEWED LTSAPSAAVT AEKNSVLPGE
RLVRNGVSWS HSSMLPLGSS LPDELLFADD SSEGSEVLM
//

MIM 604705
*RECORD*
*FIELD* NO
604705
*FIELD* TI
*604705 MER TYROSINE KINASE PROTOONCOGENE; MERTK
*FIELD* TX

CLONING

By screening a human B-lymphoblastoid lambda-gt11 expression library
read morewith 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.

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.

*FIELD* AV
.0001
RETINITIS PIGMENTOSA 38
MERTK, 5-BP DEL, NT2070

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

In a sample from a 34-year-old woman with retinitis pigmentosa (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

In a sample from a 21-year-old woman with retinitis pigmentosa (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

In 5 sibs from a consanguineous Moroccan family with retinal dystrophy
(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

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

See 604705.0003 and Mackay et al. (2010).

.0007
RETINITIS PIGMENTOSA 38
MERTK, 91-KB DEL

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

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.

*FIELD* RF
1. Angelillo-Scherrer, A.; Burnier, L.; Flores, N.; Savi, P.; DeMol,
M.; Schaeffer, P.; Herbert, J.-M.; Lemke, G.; Goff, S. P.; Matsushima,
G. K.; Earp, H. S.; Vesin, C.; Hoylaerts, M. F.; Plaisance, S.; Collen,
D.; Conway, E. M.; Wehrle-Haller, B.; Carmeliet, P.: Role of Gas6
receptors in platelet signaling during thrombus stabilization and
implications for antithrombotic therapy. J. Clin. Invest. 115: 237-246,
2005.

2. Camenisch, T. D.; Koller, B. H.; Earp, H. S.; Matsushima, G. K.
: A novel receptor tyrosine kinase, mer, inhibits TNF-alpha production
and lipopolysaccharide-induced endotoxic shock. J. Immun. 162: 3498-3503,
1999.

3. Chung, W.-S.; Clarke, L. E.; Wang, G. X.; Stafford, B. K.; Sher,
A.; Chakraborty, C.; Joung, J.; Foo, L. C.; Thompson, A.; Chen, C.;
Smith, S. J.; Barres, B. A.: Astrocytes mediate synapse elimination
through MEGF10 and MERTK pathways. Nature 504: 394-400, 2013.

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.

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.

6. Gal, A.; Li, Y.; Thompson, D. A.; Weir, J.; Orth, U.; Jacobson,
S. G.; Apfelstedt-Sylla, E.; Vollrath, D.: Mutations in MERTK, the
human orthologue of the RCS rat retinal dystrophy gene, cause retinitis
pigmentosa. Nature Genet. 26: 270-271, 2000.

7. 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.

8. 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.

9. 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.

10. 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.

11. Lu, Q.; Lemke, G.: Homeostatic regulation of the immune system
by receptor tyrosine kinases of the Tyro 3 family. Science 293:
306-311, 2001.

12. Mackay, D. S.; Henderson, R. H.; Sergouniotis, P. I.; Li, Z.;
Moradi, P.; Holder, G. E.; Waseem, N.; Bhattacharya, S. S.; Aldahmesh,
M. A.; Alkuraya, F. S.; Meyer, B.; Webster, A. R.; Moore, A. T.:
Novel mutations in MERTK associated with childhood onset rod-cone
dystrophy. Molec. Vision 16: 369-377, 2010.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

*FIELD* CN
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

*FIELD* CD
Wilson H. Y. Lo: 3/20/2000

*FIELD* ED
alopez: 01/30/2014
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
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mgross: 8/8/2001
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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

MIM 613862
*RECORD*
*FIELD* NO
613862
*FIELD* TI
#613862 RETINITIS PIGMENTOSA 38; RP38
;;ROD-CONE DYSTROPHY, CHILDHOOD-ONSET
*FIELD* TX
read moreA number sign (#) is used with this entry because this form of retinitis
pigmentosa (RP38) is caused by homozygous or compound heterozygous
mutation in the MER tyrosine kinase protooncogene (MERTK; 604705) on
chromosome 2q14.1.

DESCRIPTION

Retinitis pigmentosa (RP) describes a group of disorders with
progressive degeneration of rod and cone photoreceptors in a rod-cone
pattern of dysfunction. RP has a prevalence of 1 in 3,500, and is
genetically and phenotypically heterogeneous (summary by Mackay et al.,
2010).

For a general phenotypic description and a discussion of genetic
heterogeneity of retinitis pigmentosa, see 268000.

CLINICAL FEATURES

Gal et al. (2000) described 3 individuals with degenerative retinal
disease who carried mutation in the MERTK gene (RP38). The first 2
patients were a 45-year-old man and a 34-year-old woman who both had
onset of night blindness and poor vision in early childhood and had only
a small central island of remaining vision at the time of the report.
The third patient had had poor vision as a child and complained of night
blindness at 12 years of age. An examination at an earlier age revealed
a nondetectable rod electroretinogram and abnormally reduced visual
fields. By age 17 atrophic retinal lesions were noted on ophthalmoscopic
evaluation, but retinal blood vessels were not particularly attenuated.

Thompson et al. (2002) noted that the second patient described by Gal et
al. (2000) had general connective tissue weakness.

Ebermann et al. (2007) clinically and genetically investigated a
Moroccan family segregating both retinal dystrophy and autosomal
recessive nonsyndromic hearing loss. The presence of each of these
disorders in isolation in several family members suggested a partial
overlap of 2 nonsyndromic autosomal recessive conditions rather than a
monogenic syndrome. All affected sibs with retinal degeneration in this
family exhibited severe dysfunction of both photoreceptor systems
progressing with age, resulting in panretinal disease that involved the
macula at an early age. The proband developed loss of visual acuity,
loss of peripheral vision, and night blindness at age 11 years.
Ophthalmologic examination in the sibs showed attenuated vessels in the
fundus, pigmentary mottling, and drusen-like deposits in the macula.
Ebermann et al. (2007) classified the retinal dystrophy as 'cone-rod
dystrophy.'

Mackay et al. (2010) studied 2 brothers of Middle-Eastern origin and an
unrelated Caucasian man with childhood-onset rod-cone dystrophy and
early macular atrophy. The 26-year-old brother, diagnosed with rod-cone
dystrophy at 16 years of age, noticed night blindness and visual field
loss at 9 years, with reduced central vision at 13 years. Examination at
26 years of age revealed a visual acuity of 1.78 on the LogMAR scale and
an inability to recognize any of the plates of the HRR color vision
test. Funduscopy showed pale optic discs, attenuated vessels, macular
atrophy, and bone spicules in the mid-periphery. His younger brother had
difficulty seeing in the dark from early childhood and was diagnosed
with rod-cone dystrophy at 8 years of age. His best-corrected visual
acuity was 0.32 (LogMAR) bilaterally, with a low myopic refractive
error, mild generalized dyschromatopsia, and visual fields that were
reduced to 20 to 30 degrees bilaterally. Funduscopy revealed 'bull's
eye' macular atrophy, with bone spicules and granular appearance of the
retinal pigment epithelium (RPE) in the mid-periphery. Optical coherence
tomography (OCT) in both sibs revealed thinning of the photoreceptor
layer and multiple high-reflectance bodies below the outer limiting
membrane. The unrelated Caucasian man, who noticed nyctalopia at 12
years of age and developed photophobia soon after, was diagnosed with
rod-cone dystrophy at age 14. He had a strong family history of
red-green colorblindness, affecting a maternal uncle and grandfather and
2 cousins, and also of deafness (mother, maternal uncle, and
grandmother). At 22 years of age, he had visual acuities of 0.6 (LogMAR)
on the right and 1.0 on the left, with very poor color vision. His
hearing was normal, and visual fields were reported to be full at age
19. Funduscopy showed focal atrophy in the central macula and attenuated
vessels but very little intraretinal pigment. OCT showed thinning of the
photoreceptor layer and high reflectance bodies.

Ksantini et al. (2012) studied a consanguineous Moroccan family in which
3 sibs had the rod-cone type of retinitis pigmentosa. Salient features
included night blindness starting in early infancy, dot-like whitish
deposits in the fovea and macula corresponding to autofluorescent dots
in the youngest patients, decreased visual acuity, and cone responses
higher than rod responses on electroretinography.

MOLECULAR GENETICS

In 2 patients with retinitis pigmentosa, Gal et al. (2000) identified
homozygous mutations in the MERTK gene. The first patient, with a 5-bp
deletion (604705.0001), came from a consanguineous family. The second
patient, carrying a splice site mutation (604705.0002), had paternal
isodisomy for chromosome 2. In a third patient a nonsense mutation was
found in heterozygosity (R651X; 604705.0003); a second mutation was not
found in this individual by direct sequencing of exons 1 through 19.

In 5 Moroccan sibs with retinal dystrophy, Ebermann et al. (2007)
detected homozygosity for a novel splice site mutation in the MERTK gene
(604705.0004). Two of these sibs were also affected with congenital
progressive hearing loss (DFNB59; 610220) and carried a homozygous
mutation in the pejvakin gene (610219.0003). Ebermann et al. (2007)
stated that, in contrast to typical RP, all affected sibs in this family
exhibited an ocular phenotype corresponding to cone-rod disease (CORD),
with severe dysfunction of both photoreceptor systems that progressed
with age and resulted in panretinal disease involving the macula at an
early stage.

In a consanguineous Middle Eastern family segregating autosomal
recessive rod-cone dystrophy, Mackay et al. (2010) performed a
genomewide scan and identified 3 shared regions of homozygosity, 2 on
chromosome 2 and 1 on chromosome 10. Analysis of 3 candidate genes, RGR
(600342), PCDH21 (CDHR1; 609502), and MERTK, revealed no variants that
segregated with disease in RGR or CDHR1, but a deletion encompassing
exon 8 of the MERTK gene (604705.0005) was identified in homozygosity in
the affected sibs and in heterozygosity in their unaffected parents and
sibs. Screening of 100 UK probands with autosomal recessive retinal
dystrophies and 100 Saudi Arabian probands with RP revealed a second
Saudi Arabian family with the same exon 8 deletion. Subsequent screening
of 292 probands with either Leber congenital amaurosis (LCA; see 204000)
or childhood-onset retinal dystrophy identified a single 22-year-old
Caucasian man who carried a known MERTK nonsense mutation, R651X; direct
sequencing confirmed the R651X variant and also revealed a splice site
mutation in intron 1 (604705.0006). The second Middle Eastern family was
not available for examination, but review of clinical records showed
that 5 affected individuals had childhood-onset RP, with visual acuity
ranging from 20/50 in the first decade to hand movements only by the
third decade; macular atrophy was present from the first decade and
extensive peripheral atrophy and pigmentation. Mackay et al. (2010)
concluded that the phenotype associated with MERTK mutations is one of
childhood-onset rod-cone dystrophy and early macular atrophy, with a
distinctive OCT appearance showing evidence of debris beneath the
sensory retina.

In a study involving the genetically isolated Faroe Islands population,
Ostergaard et al. (2011) estimated the prevalence of RP to be 1 in
1,900. SNP analysis in 21 RP patients revealed a homozygous region on
chromosome 2q encompassing the MERTK gene that was common to patients in
4 families, and a 91-kb deletion in MERTK (604705.0007) was identified
in 7 (30%) of the 21 patients. The 6 homozygous patients presented with
onset of disease in the first decade of life followed by rapid
deterioration of both rod and cone photoreceptor function, and early
macular involvement was present, as seen in previously reported patients
with MERTK mutations. The 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 the 91-kb
deletion represents a founder mutation in the Faroe Islands, responsible
for about 30% of RP, and that mutations in the MERTK and CDHR1 genes
together account for more than half of RP cases in that population.

In a consanguineous Moroccan family with rod-cone dystrophy mapping to
chromosome 2, Ksantini et al. (2012) identified homozygosity for a
nonsense mutation in the MERTK gene (R775X; 604705.0008). They reviewed
the phenotype of 22 reported patients with MERTK mutations, noting that
it appears to be a rather severe retinitis pigmentosa of the rod-cone
dystrophy type, with onset in the first decade in most cases and
decrease of visual acuity after 2 years of age. Discrete dot-like
autofluorescent deposits are present in the early stages, and represent
a hallmark of MERTK-specific retinal dystrophy.

*FIELD* RF
1. 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.

2. Gal, A.; Li, Y.; Thompson, D. A.; Weir, J.; Orth, U.; Jacobson,
S. G.; Apfelstedt-Sylla, E.; Vollrath, D.: Mutations in MERTK, the
human orthologue of the RCS rat retinal dystrophy gene, cause retinitis
pigmentosa. Nature Genet. 26: 270-271, 2000.

3. 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.

4. Mackay, D. S.; Henderson, R. H.; Sergouniotis, P. I.; Li, Z.; Moradi,
P.; Holder, G. E.; Waseem, N.; Bhattacharya, S. S.; Aldahmesh, M.
A.; Alkuraya, F. S.; Meyer, B.; Webster, A. R.; Moore, A. T.: Novel
mutations in MERTK associated with childhood onset rod-cone dystrophy. Molec.
Vision 16: 369-377, 2010.

5. 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.

6. 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.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Nyctalopia;
Decreased visual acuity, progressive;
Visual fields reduced;
Color vision deficits (in some patients);
Attenuation of retinal vessels;
Pale optic discs;
Macular atrophy;
Bull's-eye macular retinal pigment epithelium changes;
Peripheral retinal atrophy;
Intraretinal pigment deposition extending to posterior pole (in some
patients);
Bone-spicule pigment depositions (in some patients);
Pigment mottling in mid-periphery (in some patients);
High reflectivity of fundus (in some patients);
Wrinkled appearance of inner retina (in some patients);
Photoreceptor layer thinned on optical coherence tomography (OCT);
Hyperreflective bodies below the outer limiting membrane on OCT;
Electroretinographic responses reduced or nonrecordable;
Autofluorescent dots in posterior pole

MISCELLANEOUS:
Onset of symptoms in early childhood

MOLECULAR BASIS:
Caused by mutation in the MER tyrosine kinase protooncogene (MERTK,
604705.0001)

*FIELD* CD
Marla J. F. O'Neill: 11/30/2012

*FIELD* ED
joanna: 11/30/2012

*FIELD* CN
Marla J. F. O'Neill - updated: 10/8/2012

*FIELD* CD
Anne M. Stumpf: 4/4/2011

*FIELD* ED
carol: 10/09/2012
carol: 10/9/2012
terry: 10/8/2012
wwang: 5/17/2011
alopez: 4/4/2011