RBCC Red Blood Cell Collection

MPL (TPOR) [Confidence: high (a blood group or CD marker)]
Thrombopoietin receptor; TPO-R (Myeloproliferative leukemia protein; Proto-oncogene c-Mpl; CD110; Flags: Precursor)

UniProt P40238
ID TPOR_HUMAN Reviewed; 635 AA.
AC P40238; Q5JUZ0;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1995, sequence version 1.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Thrombopoietin receptor;
DE Short=TPO-R;
DE AltName: Full=Myeloproliferative leukemia protein;
DE AltName: Full=Proto-oncogene c-Mpl;
DE AltName: CD_antigen=CD110;
DE Flags: Precursor;
GN Name=MPL; Synonyms=TPOR;
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] (ISOFORMS 1 AND 2).
RX PubMed=1608974; DOI=10.1073/pnas.89.12.5640;
RA Vigon I., Mornon J.-P., Cocault L., Mitjavila M.-T., Tambourin P.,
RA Gisselbrecht S., Souyri M.;
RT "Molecular cloning and characterization of MPL, the human homolog of
RT the v-mpl oncogene: identification of a member of the hematopoietic
RT growth factor receptor superfamily.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:5640-5644(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2).
RX PubMed=8020956; DOI=10.1006/geno.1994.1120;
RA Mignotte V., Vigon I., Boucher de Crevecoeur E., Romeo P.-H.,
RA Lemarchandel V., Chretien S.;
RT "Structure and transcription of the human c-mpl gene (MPL).";
RL Genomics 20:5-12(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP UBIQUITINATION AT LYS-553 AND LYS573.
RX PubMed=19880496; DOI=10.1182/blood-2009-06-227033;
RA Saur S.J., Sangkhae V., Geddis A.E., Kaushansky K., Hitchcock I.S.;
RT "Ubiquitination and degradation of the thrombopoietin receptor c-
RT Mpl.";
RL Blood 115:1254-1263(2010).
RN [6]
RP VARIANTS VAL-58 AND LYS-168.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [7]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [8]
RP INTERACTION WITH ATXN2L.
RX PubMed=11784712; DOI=10.1074/jbc.M105970200;
RA Meunier C.F., Bordereaux D., Porteu F., Gisselbrecht S., Chretien S.,
RA Courtois G.;
RT "Cloning and characterization of a family of proteins associated with
RT Mpl.";
RL J. Biol. Chem. 277:9139-9147(2002).
RN [9]
RP VARIANT THCYT2 ASN-505.
RX PubMed=14764528; DOI=10.1182/blood-2003-10-3471;
RA Ding J., Komatsu H., Wakita A., Kato-Uranishi M., Ito M., Satoh A.,
RA Tsuboi K., Nitta M., Miyazaki H., Iida S., Ueda R.;
RT "Familial essential thrombocythemia associated with a dominant-
RT positive activating mutation of the c-MPL gene, which encodes for the
RT receptor for thrombopoietin.";
RL Blood 103:4198-4200(2004).
RN [10]
RP VARIANT ASN-39, AND CHARACTERIZATION OF VARIANT ASN-39.
RX PubMed=15269348; DOI=10.1073/pnas.0404241101;
RA Moliterno A.R., Williams D.M., Gutierrez-Alamillo L.I., Salvatori R.,
RA Ingersoll R.G., Spivak J.L.;
RT "Mpl Baltimore: a thrombopoietin receptor polymorphism associated with
RT thrombocytosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:11444-11447(2004).
RN [11]
RP VARIANT MMM LYS-515.
RX PubMed=16868251; DOI=10.1182/blood-2006-04-018879;
RA Pardanani A.D., Levine R.L., Lasho T., Pikman Y., Mesa R.A.,
RA Wadleigh M., Steensma D.P., Elliott M.A., Wolanskyj A.P., Hogan W.J.,
RA McClure R.F., Litzow M.R., Gilliland D.G., Tefferi A.;
RT "MPL515 mutations in myeloproliferative and other myeloid disorders: a
RT study of 1182 patients.";
RL Blood 108:3472-3476(2006).
RN [12]
RP VARIANT MMM LEU-515, AND CHARACTERIZATION OF VARIANT MMM LEU-515.
RX PubMed=16834459; DOI=10.1371/journal.pmed.0030270;
RA Pikman Y., Lee B.H., Mercher T., McDowell E., Ebert B.L., Gozo M.,
RA Cuker A., Wernig G., Moore S., Galinsky I., DeAngelo D.J., Clark J.J.,
RA Lee S.J., Golub T.R., Wadleigh M., Gilliland D.G., Levine R.L.;
RT "MPLW515L is a novel somatic activating mutation in myelofibrosis with
RT myeloid metaplasia.";
RL PLoS Med. 3:E270-E270(2006).
RN [13]
RP CHARACTERIZATION OF VARIANT THCYT2 ASN-505.
RX PubMed=19483125; DOI=10.1182/blood-2008-04-149047;
RA Ding J., Komatsu H., Iida S., Yano H., Kusumoto S., Inagaki A.,
RA Mori F., Ri M., Ito A., Wakita A., Ishida T., Nitta M., Ueda R.;
RT "The Asn505 mutation of the c-MPL gene, which causes familial
RT essential thrombocythemia, induces autonomous homodimerization of the
RT c-Mpl protein due to strong amino acid polarity.";
RL Blood 114:3325-3328(2009).
RN [14]
RP VARIANT THCYT2 LEU-515.
RX PubMed=23441089; DOI=10.1002/pbc.24500;
RA Farruggia P., D'Angelo P., La Rosa M., Scibetta N., Santangelo G.,
RA Lo Bello A., Duner E., Randi M.L., Putti M.C., Santoro A.;
RT "MPL W515L mutation in pediatric essential thrombocythemia.";
RL Pediatr. Blood Cancer 60:E52-E54(2013).
CC -!- FUNCTION: Receptor for thrombopoietin. May represent a regulatory
CC molecule specific for TPO-R-dependent immune responses.
CC -!- SUBUNIT: Interacts with ATXN2L.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=C-mpl-P;
CC IsoId=P40238-1; Sequence=Displayed;
CC Name=2; Synonyms=C-mpl-K;
CC IsoId=P40238-2; Sequence=VSP_001734, VSP_001735;
CC -!- TISSUE SPECIFICITY: Expressed at a low level in a large number of
CC cells of hematopoietic origin. Isoform 1 and isoform 2 are always
CC found to be coexpressed.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- PTM: Ubiquitination at Lys-553 and Lys-573 targets MPL for
CC degradation by both the lysosomal and proteasomal pathways. The E3
CC ubiquitin-protein ligase CBL significantly contributes to this
CC ubiquitination.
CC -!- DISEASE: Congenital amegakaryocytic thrombocytopenia (CAMT)
CC [MIM:604498]: Disease characterized by isolated thrombocytopenia
CC and megakaryocytopenia with no physical anomalies. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Thrombocythemia 2 (THCYT2) [MIM:601977]: A
CC myeloproliferative disorder characterized by excessive platelet
CC production, resulting in increased numbers of circulating
CC platelets. It can be associated with spontaneous hemorrhages and
CC thrombotic episodes. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450]:
CC A chronic myeloproliferative disorder characterized by replacement
CC of the bone marrow by fibrous tissue, extramedullary
CC hematopoiesis, anemia, leukoerythroblastosis and
CC hepatosplenomegaly. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 1
CC subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-8 is the initiator.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MPL";
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DR EMBL; M90102; AAA69971.1; -; mRNA.
DR EMBL; M90103; AAA69972.1; -; mRNA.
DR EMBL; U68162; AAB08424.1; -; Genomic_DNA.
DR EMBL; U68159; AAB08424.1; JOINED; Genomic_DNA.
DR EMBL; U68160; AAB08424.1; JOINED; Genomic_DNA.
DR EMBL; U68161; AAB08424.1; JOINED; Genomic_DNA.
DR EMBL; U68162; AAB08425.1; -; Genomic_DNA.
DR EMBL; U68159; AAB08425.1; JOINED; Genomic_DNA.
DR EMBL; U68160; AAB08425.1; JOINED; Genomic_DNA.
DR EMBL; U68161; AAB08425.1; JOINED; Genomic_DNA.
DR EMBL; AL139289; CAI23380.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07103.1; -; Genomic_DNA.
DR PIR; A45266; A45266.
DR PIR; B45266; B45266.
DR RefSeq; NP_005364.1; NM_005373.2.
DR UniGene; Hs.82906; -.
DR ProteinModelPortal; P40238; -.
DR SMR; P40238; 22-169.
DR DIP; DIP-5730N; -.
DR IntAct; P40238; 1.
DR STRING; 9606.ENSP00000361548; -.
DR BindingDB; P40238; -.
DR ChEMBL; CHEMBL1864; -.
DR GuidetoPHARMACOLOGY; 1722; -.
DR PhosphoSite; P40238; -.
DR DMDM; 730980; -.
DR PaxDb; P40238; -.
DR PRIDE; P40238; -.
DR DNASU; 4352; -.
DR Ensembl; ENST00000372470; ENSP00000361548; ENSG00000117400.
DR GeneID; 4352; -.
DR KEGG; hsa:4352; -.
DR UCSC; uc001ciw.3; human.
DR CTD; 4352; -.
DR GeneCards; GC01P043803; -.
DR HGNC; HGNC:7217; MPL.
DR HPA; CAB002011; -.
DR HPA; HPA007619; -.
DR MIM; 159530; gene.
DR MIM; 254450; phenotype.
DR MIM; 601977; phenotype.
DR MIM; 604498; phenotype.
DR neXtProt; NX_P40238; -.
DR Orphanet; 3319; Congenital amegakaryocytic thrombocytopenia.
DR Orphanet; 3318; Essential thrombocythemia.
DR Orphanet; 71493; Familial thrombocytosis.
DR Orphanet; 824; Myelofibrosis with myeloid metaplasia.
DR Orphanet; 729; Polycythemia vera.
DR PharmGKB; PA30923; -.
DR eggNOG; NOG39882; -.
DR HOGENOM; HOG000138191; -.
DR HOVERGEN; HBG000085; -.
DR InParanoid; P40238; -.
DR KO; K05082; -.
DR OMA; QETCYQL; -.
DR PhylomeDB; P40238; -.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P40238; -.
DR GeneWiki; Thrombopoietin_receptor; -.
DR GenomeRNAi; 4352; -.
DR NextBio; 17122; -.
DR PRO; PR:P40238; -.
DR ArrayExpress; P40238; -.
DR Bgee; P40238; -.
DR CleanEx; HS_MPL; -.
DR Genevestigator; P40238; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004896; F:cytokine receptor activity; IEA:InterPro.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc.
DR GO; GO:0008283; P:cell proliferation; TAS:ProtInc.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:GOC.
DR GO; GO:0048872; P:homeostasis of number of cells; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0032642; P:regulation of chemokine production; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 4.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR015152; Growth/epo_recpt_lig-bind.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003528; Long_hematopoietin_rcpt_CS.
DR Pfam; PF09067; EpoR_lig-bind; 1.
DR Pfam; PF00041; fn3; 1.
DR SMART; SM00060; FN3; 2.
DR SUPFAM; SSF49265; SSF49265; 4.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS01352; HEMATOPO_REC_L_F1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Disulfide bond; Glycoprotein; Isopeptide bond; Membrane; Polymorphism;
KW Receptor; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT SIGNAL 1 25 Potential.
FT CHAIN 26 635 Thrombopoietin receptor.
FT /FTId=PRO_0000010987.
FT TOPO_DOM 26 491 Extracellular (Potential).
FT TRANSMEM 492 513 Helical; (Potential).
FT TOPO_DOM 514 635 Cytoplasmic (Potential).
FT DOMAIN 172 281 Fibronectin type-III 1.
FT DOMAIN 392 486 Fibronectin type-III 2.
FT MOTIF 474 478 WSXWS motif.
FT MOTIF 528 536 Box 1 motif.
FT COMPBIAS 335 338 Poly-Glu.
FT COMPBIAS 508 513 Poly-Leu.
FT CARBOHYD 117 117 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 178 178 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 298 298 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 358 358 N-linked (GlcNAc...) (Potential).
FT DISULFID 40 50 By similarity.
FT DISULFID 77 93 By similarity.
FT DISULFID 291 301 By similarity.
FT DISULFID 323 334 By similarity.
FT CROSSLNK 553 553 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 573 573 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 523 579 RLRHALWPSLPDLHRVLGQYLRDTAALSPPKATVSDTCEEV
FT EPSLLEILPKSSERTP -> YRPRQAGDWRWTRWSRTCKQA
FT FLVRSVTPDLRPPPVRTYGFALPARHLWDSPRLLTL (in
FT isoform 2).
FT /FTId=VSP_001734.
FT VAR_SEQ 580 635 Missing (in isoform 2).
FT /FTId=VSP_001735.
FT VARIANT 39 39 K -> N (functional polymorphism
FT associated with thrombocytosis; results
FT in altered MPL expression;
FT dbSNP:rs17292650).
FT /FTId=VAR_049173.
FT VARIANT 58 58 A -> V (in dbSNP:rs6087).
FT /FTId=VAR_011988.
FT VARIANT 114 114 V -> M (in dbSNP:rs12731981).
FT /FTId=VAR_049174.
FT VARIANT 168 168 E -> K (in dbSNP:rs6088).
FT /FTId=VAR_011989.
FT VARIANT 505 505 S -> N (in THCYT2; activating mutation;
FT induces MPL autonomous dimerization and
FT signal activation in the absence of the
FT ligand; dbSNP:rs121913614).
FT /FTId=VAR_067559.
FT VARIANT 515 515 W -> K (in MMM; somatic mutation;
FT requires 2 nucleotide substitutions).
FT /FTId=VAR_067560.
FT VARIANT 515 515 W -> L (in THCYT2 and MMM; somatic
FT mutation in myelofibrosis with myeloid
FT metaplasia; results in cytokine-
FT independent growth and thrombopoietin
FT hypersensitivity; results in constitutive
FT activation of JAK-STAT signaling pathway;
FT dbSNP:rs121913615).
FT /FTId=VAR_067561.
SQ SEQUENCE 635 AA; 71245 MW; D25D8D8959359DDC CRC64;
MPSWALFMVT SCLLLAPQNL AQVSSQDVSL LASDSEPLKC FSRTFEDLTC FWDEEEAAPS
GTYQLLYAYP REKPRACPLS SQSMPHFGTR YVCQFPDQEE VRLFFPLHLW VKNVFLNQTR
TQRVLFVDSV GLPAPPSIIK AMGGSQPGEL QISWEEPAPE ISDFLRYELR YGPRDPKNST
GPTVIQLIAT ETCCPALQRP HSASALDQSP CAQPTMPWQD GPKQTSPSRE ASALTAEGGS
CLISGLQPGN SYWLQLRSEP DGISLGGSWG SWSLPVTVDL PGDAVALGLQ CFTLDLKNVT
CQWQQQDHAS SQGFFYHSRA RCCPRDRYPI WENCEEEEKT NPGLQTPQFS RCHFKSRNDS
IIHILVEVTT APGTVHSYLG SPFWIHQAVR LPTPNLHWRE ISSGHLELEW QHPSSWAAQE
TCYQLRYTGE GHQDWKVLEP PLGARGGTLE LRPRSRYRLQ LRARLNGPTY QGPWSSWSDP
TRVETATETA WISLVTALHL VLGLSAVLGL LLLRWQFPAH YRRLRHALWP SLPDLHRVLG
QYLRDTAALS PPKATVSDTC EEVEPSLLEI LPKSSERTPL PLCSSQAQMD YRRLQPSCLG
TMPLSVCPPM AESGSCCTTH IANHSYLPLS YWQQP
//

MIM 159530
*RECORD*
*FIELD* NO
159530
*FIELD* TI
*159530 MYELOPROLIFERATIVE LEUKEMIA VIRUS ONCOGENE; MPL
;;THROMBOPOIETIN RECEPTOR; TPOR;;
read moreMYELOPROLIFERATIVE LEUKEMIA VIRUS, MOUSE, HOMOLOG OF; MPLV
*FIELD* TX

DESCRIPTION

The MPL gene encodes the receptor for thrombopoietin (THPO; 600044), a
hematopoietic growth factor that regulates the production of multipotent
hematopoietic progenitor cells and platelets.

Penciolelli et al. (1987) first identified this protein as a murine
retrovirus that causes mouse acute leukemia, and was thus given the name
'myeloproliferative leukemia virus' (MPLV). The phenotype in mice was
characterized by rapid proliferation of erythrocytic, granulocytic, and
megakaryocytic progenitor cells, resulting in polycythemia,
thrombocytosis, and hepatosplenomegaly. MPLV was shown to be a
replication-defective, nonsarcomatogenic retrovirus.

CLONING

Vigon et al. (1992) cloned the human homolog of the v-mpl oncogene and
found that it showed striking homology with members of the hematopoietin
receptor superfamily. They obtained 2 types of clones, termed MPLP and
MPLK, which had the same 5-prime extremity but differed in their 3-prime
ends. The 2 clones were predicted to encode 635- and 572-residue
proteins, respectively. The resulting deduced polypeptides contained a
common extracellular domain with a putative signal sequence and a common
transmembrane domain but differed in their cytoplasmic domain. The
extracellular domain of MPL contains the consensus sequences described
for members of the hematopoietin receptor superfamily which include IL5R
(147851), IL3RA (308385), IL4R (147781), IL7R (146661), IL2RB (146710),
erythropoietin receptor (EPOR; 133171), IL6R (147880), GMCSF receptor
(CSF2R; 306250), and CSF3R (138971). It also shows similarities to the
growth hormone receptor (GHR; 600946) and the prolactin receptor (PRLR;
176761). Northern blot analysis of a human erythroleukemia cell line
identified 2 MPL mRNA transcripts: a major 3.7-kb (MPLP) transcript and
a minor 2.8-kb (MPLK) transcript.

Mignotte et al. (1994) described 3 types of mRNA encoding different MPL
proteins generated by alternative splicing: the major species contains
all 12 exons, whereas mRNAs encoding a protein with a smaller
cytoplasmic domain are produced by termination of the transcript within
intron 10, and mRNAs encoding a putative soluble form of the MPL protein
lack exons 9 and 10. The promoter region is GC-rich and contains
putative binding sites for proteins of the ETS and GATA families.

GENE STRUCTURE

Mignotte et al. (1994) demonstrated that the MPL gene contains 12 exons
distributed over 17 kb of DNA. Each of the 2 'cytokine receptor domains'
of MPL is encoded by a set of 4 exons, the transmembrane by a single
exon, and the cytoplasmic domain by 2 exons.

MAPPING

By means of in situ hybridization, Le Coniat et al. (1989) mapped the
human MPL gene to chromosome 1p34.

GENE FUNCTION

The mechanism by which TPO activates the TPO receptor appears to be
similar to that of other hematopoietic cytokines that bind and induce
receptor homodimerization. Cwirla et al. (1997) identified 2 families of
small peptides that bound to human TPOR and competed with the binding of
the natural ligand TPO. The sequences of these peptides were not found
in the primary sequence of TPO. Further specific screening identified a
14-amino acid peptide with high affinity that stimulated the
proliferation of a TPO-responsive cell line. A dimer derived from this
peptide stimulated the in vitro proliferation and maturation of
megakaryocytes from human bone marrow cells and promoted an increase in
platelet count when administered to normal mice. The findings could aid
in the development of a recombinant human TPO used for the treatment of
thrombocytopenia resulting from chemotherapy and bone marrow
transplantation.

Moliterno et al. (1998) found that MPL was markedly reduced or absent in
platelets of all 34 patients with polycythemia vera (PV; 263300) and in
13 of 14 patients with idiopathic myelofibrosis (254450). This
abnormality appeared to distinguish polycythemia vera from other forms
of erythrocytosis.

Akashi et al. (2000) identified a common myeloid progenitor cell that
gives rise to all myeloid lineages. The myeloid progenitor did not
express IL7R, but did express MPL, whereas the common lymphoid
progenitor expressed IL7R but not MPL. Further differentiation of the
common myeloid progenitor into the granulocyte/monocyte progenitor
versus the megakaryocyte/erythrocyte progenitor was found to be
dependent upon expression of the erythropoietin receptor. The commitment
of the common myeloid progenitors to either the
megakaryocyte/erythrocyte or the granulocyte/macrophage lineages was
proposed to be a mutually exclusive event.

MOLECULAR GENETICS

- Congenital Amegakaryocytic Thrombocytopenia

The considerable similarities between human congenital amegakaryocytic
thrombocytopenia (CAMT; 604498) and murine mpl deficiency prompted Ihara
et al. (1999) to analyze the MPL gene in a patient with CAMT. DNA
studies detected compound heterozygosity for 2 mutations in the gene
(159530.0001; 159530.0002), both of which were predicted to result in a
prematurely terminated MPL protein, which, if translated, would lack all
intracellular domains essential for signal transduction. The parents
were heterozygous for the mutations.

In 8 CAMT patients, Ballmaier et al. (2001) identified homozygous or
compound heterozygous mutations in the MPL gene (see, e.g., 159530.0005;
159530.0008). Five patients had complete loss of MPL function, and 3 had
missense mutations that were predicted to affect the extracellular
domain. Four of the patients were of Kurdish origin and had
consanguineous parents. Although all patients had high serum TPO levels,
platelets and hematopoietic progenitor cells showed no reactivity to
TPO, as measured by testing TPO-synergism to adenosine diphosphate in
platelet activation or by megakaryocyte colony assays. Flow cytometry
revealed absent surface expression of the TPO receptor MPL in all 3
patients analyzed.

- Role in Myeloproliferative Disorders

Moliterno et al. (2004) identified a heterozygous SNP in the MPL gene
(K39N; 159530.0009), designated 'MPL Baltimore,' in approximately 7% of
African Americans. Three African American women referred for evaluation
of a chronic myeloproliferative disorder (MPD) were found to be
heterozygous for K39N. Further studies showed that African Americans
with the K39N polymorphism had a significantly higher platelet count
than controls without the polymorphism (p less than 0.001) and reduced
platelet protein MPL expression. Expression of MPL cDNA containing the
K39N substitution in cell lines was associated with incomplete
processing and a reduction in MPL protein. Moliterno et al. (2004)
concluded that K39N represents a functional MPL polymorphism and is
associated with altered protein expression of the thrombopoietin
receptor and a clinical phenotype of thrombocytosis (THCYT2; 601977).
Individuals who were homozygous for K39N individuals exhibited severe
thrombocytosis when compared with appropriate controls. Moliterno et al.
(2004) noted that impaired MPL function in the setting of thrombocytosis
is counterintuitive, given the phenotype of marked thrombocytopenia in
individuals with loss-of-function MPL mutations, but the authors
suggested that MPL may also have a negative regulatory role. The K39N
substitution was restricted to African Americans.

In affected members of a Japanese family with autosomal dominant
essential thrombocythemia, Ding et al. (2004) identified a heterozygous
activating germline mutation in the MPL gene (159530.0010).

Pikman et al. (2006) and Pardanani et al. (2006) independently
identified gain-of-function somatic mutations in codon 515 of the MPL
gene (W515L, 159530.0011; W515K, 159530.0012) in patients with
myelofibrosis with myeloid metaplasia (see 254450) and/or essential
thrombocythemia.

ANIMAL MODEL

Gurney et al. (1994) found that Mpl-null mice had an 85% decrease in the
number of platelets and megakaryocytes but had normal amounts of other
hematopoietic cell types. These mice also had increased concentrations
of circulating TPO. These results showed that MPL specifically regulates
megakaryocytopoiesis and thrombopoiesis through activation by its ligand
TPO.

Kimura et al. (1998) found that mice lacking Mpl have hematopoietic stem
cell deficiencies that are not limited to the megakaryocytic lineage.
Their findings imply that TPO, signaling through MPL, plays a vital
physiologic role in the regulation of hematopoietic stem cell production
and function.

Carpinelli et al. (2004) performed a suppressor screen in Mpl-null mice
using N-ethyl-N-nitrosourea (ENU) mutagenesis. They showed that
mutations in the Myb gene (189990) caused a myeloproliferative syndrome
and supraphysiologic expansion of megakaryocyte and platelet production
in the absence of thrombopoietin signaling.

*FIELD* AV
.0001
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, GLN186TER

In a patient with congenital amegakaryocytic thrombocytopenia (604498),
Ihara et al. (1999) identified compound heterozygosity for 2 mutations
in the MPL gene: a 556C-T transition in exon 4 resulting in a
gln186-to-ter (Q186X) substitution, and a 1-bp deletion in exon 10
(1499delT; 159530.0002) resulting in a frameshift and premature stop
codon.

.0002
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, 1-BP DEL, 1499T

See 159530.0001 and Ihara et al. (1999).

.0003
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, ARG257CYS

In a 2-year-old Italian boy with congenital amegakaryocytic
thrombocytopenia (604498), Tonelli et al. (2000) found compound
heterozygosity for 2 MPL mutations. One allele carried a 769C-T
transition in exon 5, resulting in an arg257-to-cys (R257C) substitution
in the extracellular domain, 11 amino acids distant from the WSXWS motif
conserved in the cytokine-receptor superfamily. The other allele carried
a 1904C-T transition in exon 12, resulting in a pro635-to-leu (P635L;
159530.0004) substitution in the last amino acid of the C-terminal
intracellular domain, responsible for signal transduction. TPO plasma
levels were greatly increased in the patient. The same patient appears
to have been reported by van den Oudenrijn et al. (2000).

By in vitro cellular studies in K562 human leukemia cells, Tijssen et
al. (2008) demonstrated that the R257C mutant was expressed at the cell
surface but resulted in significantly impaired TPO signal transduction.

.0004
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, PRO635LEU

See 159530.0003 and Tonelli et al. (2000).

By in vitro cellular studies in K562 human leukemia cells, Tijssen et
al. (2008) demonstrated that the P635L mutant was not properly expressed
at the cell surface and resulted in significantly impaired TPO signal
transduction.

.0005
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, ARG102PRO

In a patient with CAMT (604498), van den Oudenrijn et al. (2000) found
compound heterozygosity for 2 mutations in the MPL gene: a 305G-C
mutation in exon 3, resulting in an arg102-to-pro (R102P) substitution,
and a 1473G-A mutation in exon 10 resulting in a trp491-to-ter (W491X;
159530.0006) substitution. The R102P substitution occurs in the
extracellular part of the protein. The patient had low platelet counts
from birth onwards, but relatively late development of anemia and
leukopenia, consistent with the milder type II phenotype.

By in vitro cellular studies in K562 human leukemia cells, Tijssen et
al. (2008) demonstrated that the R102P mutant was expressed at the cell
surface but resulted in impaired TPO signal transduction.

.0006
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, TRP491TER

See 159530.0005 and van den Oudenrijn et al. (2000).

.0007
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, IVS10AS, G-T, -1

In a patient with CAMT (604498), van den Oudenrijn et al. (2000) found
homozygosity for a G-to-T transversion in the last base of intron 10 of
the MPL gene, resulting in loss of the splice site 5-prime of exon 11.

.0008
AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL
MPL, PRO275THR

In a patient with CAMT (604498), Ballmaier et al. (2001) found compound
heterozygosity for 2 mutations in the MPL gene: an 823C-A transversion
in exon 5 resulting in a pro275-to-thr (P275T) substitution, and R102P
(159530.0005).

.0009
THROMBOCYTHEMIA 2, SUSCEPTIBILITY TO
MPL, LYS39ASN

Moliterno et al. (2004) found that approximately 7% of African Americans
are heterozygous for a single nucleotide substitution in the MPL gene,
1238G-T, which results in a lys39-to-asn substitution (K39N). African
Americans with the K39N polymorphism, which the authors designated MPL
Baltimore, had a significantly higher platelet count than controls
without the polymorphism (p less than 0.001) and reduced platelet
protein MPL expression. Moliterno et al. (2004) concluded that K39N
represents a functional MPL polymorphism and is associated with altered
protein expression of the thrombopoietin receptor and a clinical
phenotype of thrombocytosis (601977). Individuals who were homozygous
for K39N individuals exhibited severe thrombocytosis when compared with
appropriate controls. Moliterno et al. (2004) noted that impaired MPL
function in the setting of thrombocytosis is counterintuitive, given the
phenotype of marked thrombocytopenia in individuals with
loss-of-function MPL mutations, but the authors suggested that MPL may
also have a negative regulatory role.

.0010
THROMBOCYTHEMIA 2
MPL, SER505ASN

In affected members of a Japanese family with autosomal dominant
thrombocythemia-2 (601977), Ding et al. (2004) identified a heterozygous
1073G-A transition in exon 10 of the MPL gene, resulting in a
ser505-to-asn (S505N) substitution. Cellular studies showed that mutant
cells had increased cytokine-independent survival and constitutively
phosphorylated Mek1/2 (see, e.g., 176872), suggesting that S505N is an
activating mutation.

Ding et al. (2009) found that, due to the strong polarity of asparagine,
the S505N substitution induced autonomous dimerization of mutant MPL,
permitting signal activation in the absence of ligand.

.0011
MYELOFIBROSIS WITH MYELOID METAPLASIA, SOMATIC
THROMBOCYTHEMIA 2, SOMATIC, INCLUDED
MPL, TRP515LEU

Pikman et al. (2006) identified a somatic 1544G-T transversion in the
MPL gene, resulting in a trp515-to-leu (W515L) substitution, in 4 (9%)
of 45 patients with myelofibrosis with myeloid metaplasia (see 254450).
Two of the patients also had leukocytosis and thrombocytosis at the time
of disease presentation. Functional expression studies showed that this
was an activating mutation conferring cytokine-independent growth and
hypersensitivity to TPHO in cell culture. The W515L mutant protein
resulted in constitutive phosphorylation of downstream signaling
molecules, including JAK2 (147796), STAT3 (102582), and ERK (600997).
Expression of W515L in murine bone marrow resulted in a fully penetrant
myeloproliferative disorder with thrombocytosis and extramedullary
hematopoiesis.

Pardanani et al. (2006) identified a somatic W515L mutation in 9
patients with myelofibrosis with myeloid metaplasia and in 4 with
essential thrombocythemia (601977). Six of these patients were also
heterozygous for the JAK2 V617F mutation (147796.0001), 2 of whom also
carried the MPL W515K mutation (159530.0012)

.0012
MYELOFIBROSIS WITH MYELOID METAPLASIA, SOMATIC
MPL, TRP515LYS

Pardanani et al. (2006) identified a TG-to-AA mutation in the MPL gene,
resulting in a somatic trp515-to-lys (W515K) substitution, in 5 patients
with myelofibrosis with myeloid metaplasia (see 254450). Two of the
patients also had the W515L mutation (159530.0011) and the JAK2 V617F
mutation (147796.0001).

*FIELD* RF
1. Akashi, K.; Traver, D.; Miyamoto, T.; Weissman, I. L.: A clonogenic
common myeloid progenitor that gives rise to all myeloid lineages. Nature 404:
193-197, 2000.

2. Ballmaier, M.; Germeshausen, M.; Schulze, H.; Cherkaoui, K.; Lang,
S.; Gaudig, A.; Krukemeier, S.; Eilers, M.; Straub, G.; Welte, K.
: c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 97:
139-146, 2001.

3. Carpinelli, M. R.; Hilton, D. J.; Metcalf, D.; Antonchuk, J. L.;
Hyland, C. D.; Mifsud, S. L.; Di Rago, L.; Hilton, A. A.; Willson,
T. A.; Roberts, A. W.; Ramsay, R. G.; Nicola, N. A.; Alexander, W.
S.: Suppressor screen in Mpl -/- mice: c-Myb mutation causes supraphysiological
production of platelets in the absence of thrombopoietin signaling. Proc.
Nat. Acad. Sci. 101: 6553-6558, 2004.

4. Cwirla, S. E.; Balasubramanian, P.; Duffin, D. J.; Wagstrom, C.
R.; Gates, C. M.; Singer, S. C.; Davis, A. M.; Tansik, R. L.; Mattheakis,
L. C.; Boytos, C. M.; Schatz, P. J.; Baccanari, D. P.; Wrighton, N.
C.; Barrett, R. W.; Dower, W. J.: Peptide agonist of the thrombopoietin
receptor as potent as the natural cytokine. Science 276: 1696-1699,
1997.

5. Ding, J.; Komatsu, H.; Iida, S.; Yano, H.; Kusumoto, S.; Inagaki,
A.; Mori, F.; Ri, M.; Ito, A.; Wakita, A.; Ishida, T.; Nitta, M.;
Ueda, R.: The asn505 mutation of the c-MPL gene, which causes familial
essential thrombocythemia, induces autonomous homodimerization of
the c-Mpl protein due to strong amino acid polarity. Blood 114:
3325-3328, 2009.

6. Ding, J.; Komatsu, H.; Wakita, A.; Kato-Uranishi, M.; Ito, M.;
Satoh, A.; Tsuboi, K.; Nitta, M.; Miyazaki, H.; Iida, S.; Ueda, R.
: Familial essential thrombocythemia associated with a dominant-positive
activating mutation of the c-MPL gene, which encodes for the receptor
for thrombopoietin. Blood 103: 4198-4200, 2004.

7. Gurney, A. L.; Carver-Moore, K.; de Sauvage, F. J.; Moore, M. W.
: Thrombocytopenia in c-mpl-deficient mice. Science 265: 1445-1447,
1994.

8. Ihara, K.; Ishii, E.; Eguchi, M.; Takada, H.; Suminoe, A.; Good,
R. A.; Hara, T.: Identification of mutations in the c-mpl gene in
congenital amegakaryocytic thrombocytopenia. Proc. Nat. Acad. Sci. 96:
3132-3136, 1999.

9. Kimura, S.; Roberts, A. W.; Metcalf, D.; Alexander, W. S.: Hematopoietic
stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc.
Nat. Acad. Sci. 95: 1195-1200, 1998.

10. Le Coniat, M.; Souyri, M.; Vigon, I.; Wendling, F.; Tambourin,
P.; Berger, R.: The human homolog of the myeloproliferative virus
maps to chromosome band 1p34. Hum. Genet. 83: 194-196, 1989.

11. Mignotte, V.; Vigon, I.; Boucher de Crevecoeur, E.; Romeo, P.-H.;
Lemarchandel, V.; Chretien, S.: Structure and transcription of the
human c-mpl gene (MPL). Genomics 20: 5-12, 1994.

12. Moliterno, A. R.; Hankins, W. D.; Spivak, J. L.: Impaired expression
of the thrombopoietin receptor by platelets from patients with polycythemia
vera. New Eng. J. Med. 338: 572-580, 1998.

13. Moliterno, A. R.; Williams, D. M.; Gutierrez-Alamillo, L. I.;
Salvatori, R.; Ingersoll, R. G.; Spivak, J. L.: Mpl Baltimore: a
thrombopoietin receptor polymorphism associated with thrombocytosis. Proc.
Nat. Acad. Sci. 101: 11444-11447, 2004.

14. Pardanani, A. D.; Levine, R. L.; Lasho, T.; Pikman, Y.; Mesa,
R. A.; Wadleigh, M.; Steensma, D. P.; Elliott, M. A.; Wolanskyj, A.
P.; Hogan, W. J.; McClure, R. F.; Litzow, M. R.; Gilliland, D. G.;
Tefferi, A.: MPL515 mutations in myeloproliferative and other myeloid
disorders: a study of 1182 patients. Blood 108: 3472-3476, 2006.

15. Penciolelli, J. F.; Wendling, F.; Robert-Lezenes, J.; Barque,
J. F.; Tambourin, P.; Gisselbrecht, S.: Genetic analysis of myeloproliferative
leukemia virus, a novel acute leukemogenic replication-defective retrovirus. J.
Virol. 61: 579-583, 1987.

16. Pikman, Y.; Lee, B. H.; Mercher, T.; McDowell, E.; Ebert, B. L.;
Gozo, M.; Cuker, A.; Wernig, G.; Moore, S.; Galinsky, I.; DeAngelo,
D. J.; Clark, J. J.; Lee, S. J.; Golub, T. R.; Wadleigh, M.; Gilliland,
D. G.; Levine, R. L.: MPLW515L is a novel somatic activating mutation
in myelofibrosis with myeloid metaplasia. PLoS Med. 3: e270, 2006.
Note: Electronic Article.

17. Tijssen, M. R.; di Summa, F.; van den Oudenrijn, S.; Zwaginga,
J. J.; van der Schoot, C. E.; Voermans, C.; de Haas, M.: Functional
analysis of single amino-acid mutations in the thrombopoietin-receptor
Mpl underlying congenital amegakaryocytic thrombocytopenia. Brit.
J. Haematol. 141: 808-813, 2008.

18. Tonelli, R.; Scardovi, A. L.; Pession, A.; Strippoli, P.; Bonsi,
L.; Vitale, L.; Prete, A.; Locatelli, F.; Bagnara, G. P.; Paolucci,
G.: Compound heterozygosity for two different amino-acid substitution
mutations in the thrombopoietin receptor (c-mpl gene) in congenital
amegakaryocytic thrombocytopenia (CAMT). Hum. Genet. 107: 225-233,
2000.

19. van den Oudenrijn, S.; Bruin, M.; Folman, C. C.; Peters, M.; Faulkner,
L. B.; de Haas, M.; van dem Borne, A. E. G. K.: Mutations in the
thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic
thrombocytopenia. Brit. J. Haemat. 110: 441-448, 2000.

20. Vigon, I.; Mornon, J.-P.; Cocault, L.; Mitjavila, M.-T.; Tambourin,
P.; Gisselbrecht, S.; Souyri, M.: Molecular cloning and characterization
of MPL, the human homolog of the v-mpl oncogene: identification of
a member of the hematopoietic growth factor receptor superfamily. Proc.
Nat. Acad. Sci. 89: 5640-5644, 1992.

*FIELD* CN
Cassandra L. Kniffin - updated: 03/09/2012
Patricia A. Hartz - updated: 1/6/2011
Cassandra L. Kniffin - updated: 2/5/2009
Cassandra L. Kniffin - reorganized: 4/7/2008
Cassandra L. Kniffin - updated: 3/27/2008
Victor A. McKusick - updated: 10/4/2004
Victor A. McKusick - updated: 7/8/2004
Victor A. McKusick - updated: 8/17/2001
Victor A. McKusick - updated: 11/29/2000
Victor A. McKusick - updated: 10/3/2000
Ada Hamosh - updated: 3/10/2000
Victor A. McKusick - updated: 4/20/1999
Victor A. McKusick - updated: 3/12/1998
Victor A. McKusick - updated: 6/12/1997

*FIELD* CD
Victor A. McKusick: 10/12/1989

*FIELD* ED
carol: 03/09/2012
ckniffin: 3/8/2012
mgross: 1/6/2011
terry: 1/6/2011
wwang: 2/17/2009
ckniffin: 2/5/2009
carol: 9/15/2008
carol: 6/18/2008
carol: 4/18/2008
carol: 4/8/2008
carol: 4/7/2008
ckniffin: 3/27/2008
carol: 2/8/2007
terry: 3/16/2005
tkritzer: 10/8/2004
terry: 10/4/2004
tkritzer: 7/20/2004
tkritzer: 7/8/2004
terry: 7/8/2004
mcapotos: 8/28/2001
mcapotos: 8/17/2001
mcapotos: 12/18/2000
mcapotos: 12/13/2000
terry: 11/29/2000
mcapotos: 10/12/2000
mcapotos: 10/9/2000
terry: 10/3/2000
alopez: 3/10/2000
mgross: 2/4/2000
jlewis: 7/27/1999
mgross: 4/27/1999
mgross: 4/22/1999
terry: 4/20/1999
psherman: 3/12/1998
terry: 3/6/1998
mark: 6/12/1997
terry: 6/10/1997
mimadm: 12/2/1994
carol: 9/22/1994
carol: 10/1/1993
carol: 7/7/1992
supermim: 3/16/1992
carol: 6/24/1991

MIM 254450
*RECORD*
*FIELD* NO
254450
*FIELD* TI
#254450 MYELOFIBROSIS
MYELOFIBROSIS WITH MYELOID METAPLASIA, INCLUDED; MMM, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that many
cases of myelofibrosis are associated with a somatic mutation in the
JAK2 gene (147796) on chromosome 9p, somatic mutation in the MPL gene
(159530) on 1p34, or somatic mutation in the CALR gene (109091) on
chromosome 19p13.

Somatic mutations in the TET2 gene (612839), the ASXL1 gene (612990),
the SH2B3 gene (605093), the SF3B1 gene (605590), and the NFE2 gene
(601490) have also been found in cases of myelofibrosis.

CLINICAL FEATURES

Sieff and Malleson (1980) described a brother and sister who developed
fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The
bone marrow showed reduced hemopoiesis with generalized fibrosis.
Although clinically resembling familial hemophagocytic reticulosis, the
disorder did not show the characteristic hemophagocytosis as a prominent
feature. The parents were not related.

Bonduel et al. (1998) reported 2 sisters, born of nonconsanguineous
parents, with idiopathic myelofibrosis and multiple hemangiomas. The
older sister presented at 4 years of age with pallor, weakness, and
purpura; the younger sister was hospitalized at 7 months of age because
of fever and splenomegaly. Multiple small hemangiomas were pictured on
the neck and back of the older sister.

MOLECULAR GENETICS

Baxter et al. (2005) and Kralovics et al. (2005) found that 50% (8 of
16) and 57% (13 of 23) of patients with idiopathic myelofibrosis,
respectively, carried a somatic mutation in the JAK2 gene (V617F;
147796.0001).

Pikman et al. (2006) identified a somatic mutation in the MPL gene
(W515L; 159530.0011) in 4 (9%) of 45 patients with myelofibrosis with
myeloid metaplasia (MMM). Two of the patients also had leukocytosis and
thrombocytosis at the time of disease presentation. Functional
expression studies showed that this was an activating mutation
conferring cytokine-independent growth and hypersensitivity to
thrombopoietin (THPO; 600044) in cell culture. Pardanani et al. (2006)
identified somatic mutations in the MPL gene (W515L and W515K;
159530.0011) in 9 patients with myelofibrosis with myeloid metaplasia.
Some of these patients were also heterozygous for the JAK2 V617F
mutation.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 4 patients with primary myelofibrosis, 3 of whom also displayed the
JAK2 V617F mutation.

Jutzi et al. (2013) identified 7 different somatic insertion or deletion
mutations in the NFE2 gene (601490) in 8 patients with
myeloproliferative disorders, including 3 with polycythemia vera (PV;
263300) and 5 with myelofibrosis, either primary or secondary. In vitro
studies showed that the mutant truncated NFE2 proteins were unable to
bind DNA and had lost reporter gene activity. However, coexpression of
mutant NFE2 constructs with wildtype NFE2 resulted in significantly
enhanced transcriptional activity. Analysis of patient cells showed low
levels of the mutant truncated protein, but increased levels of the
wildtype NFE2 protein compared to control cells, likely due to both
increased mRNA and increased stability of the wildtype protein. All 7
patients tested also carried a JAK2 V617F mutation (147796.0001).
Hematopoietic cell colonies grown from 3 patients showed that the NFE2
mutation was acquired subsequent to the JAK2 mutation, and further
cellular studies indicated that an NFE2 mutation conferred a
proliferative advantage of cells compared to cells carrying only the
JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the
proportion of cells in the S phase, consistent with enhanced cell
division and proliferation, and this was associated with higher levels
of cell cycle regulators. These findings were replicated in mice
carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis,
and neutrophilia.

ANIMAL MODEL

Kaufmann et al. (2012) found that mice with overexpression of the Nfe2
gene in hematopoietic cells developed features of myeloproliferative
disorders, including thrombocytosis, leukocytosis, Epo-independent
colony formation, characteristic bone marrow histology, expansion of
stem and progenitor compartments, and spontaneous transformation to
acute myeloid leukemia. This phenotype was transplantable to secondary
recipient mice. Cells from Nfe2 transgenic mice showed hypoacetylation
of histone H3 (602810). Treatment of mice with a histone deacetylase
inhibitor (HDAC-I) restored physiologic levels of histone H3
acetylation, decreased Nfe2 expression, and normalized platelet numbers.
Similarly, patients with myeloproliferative disorders treated with an
HDAC-I showed a decrease in NFE2 expression. These data established a
role for aberrant NFE2 expression in the pathophysiology of
myeloproliferative disorders.

*FIELD* RF
1. Baxter, E. J.; Scott, L. M.; Campbell, P. J.; East, C.; Fourouclas,
N.; Swanton, S.; Vassiliou, G. S.; Bench, A. J.; Boyd, E. M.; Curtin,
N.; Scott, M. A.; Erber, W. N.; Cancer Genome Project; Green, A.
R.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative
disorders. Lancet 365: 1054-1061, 2005. Note: Erratum: Lancet 366:
122 only, 2005.

2. Bonduel, M.; Sciuccati, G.; Torres, A. F.; Pierini, A.; Galla,
G.: Familial idiopathic myelofibrosis and multiple hemangiomas. Am.
J. Hemat. 59: 175-177, 1998.

3. Delhommeau, F.; Dupont, S.; Della Valle, V.; James, C.; Trannoy,
S.; Masse, A.; Kosmider, O.; Le Couedic, J.-P.; Robert, F.; Alberdi,
A.; Lecluse, Y.; Plo, I.; and 11 others: Mutation in TET2 in myeloid
cancers. New Eng. J. Med. 360: 2289-2301, 2009.

4. Jutzi, J. S.; Bogeska, R.; Nikoloski, G.; Schmid, C. A.; Seeger,
T. S.; Stegelmann, F.; Schwemmers, S.; Grunder, A.; Peeken, J. C.;
Gothwal, M.; Wehrle, J.; Aumann, K.; Hamdi, K.; Dierks, C.; Wang,
W.; Dohner, K.; Jansen, J. H.; Pahl, H. L.: MPN patients harbor recurrent
truncating mutations in transcription factor NF-E2. J. Exp. Med. 210:
1003-1019, 2013.

5. Kaufmann, K. B.; Grunder, A.; Hadlich, T.; Wehrle, J.; Gothwal,
M.; Bogeska, R.; Seeger, T. S.; Kayser, S.; Pham, K.-B.; Jutzi, J.
S.; Ganzenmuller, L.; Steinemann, D.; and 11 others: A novel murine
model of myeloproliferative disorders generated by overexpression
of the transcription factor NF-E2. J. Exp. Med. 209: 35-50, 2012.

6. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt,
R.; Passweg, J. R.; Tichelli, A.; Cazzola, M.; Skoda, R. C.: A gain-of-function
mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352:
1779-1790, 2005.

7. Pardanani, A. D.; Levine, R. L.; Lasho, T.; Pikman, Y.; Mesa, R.
A.; Wadleigh, M.; Steensma, D. P.; Elliott, M. A.; Wolanskyj, A. P.;
Hogan, W. J.; McClure, R. F.; Litzow, M. R.; Gilliland, D. G.; Tefferi,
A.: MPL515 mutations in myeloproliferative and other myeloid disorders:
a study of 1182 patients. Blood 108: 3472-3476, 2006.

8. Pikman, Y.; Lee, B. H.; Mercher, T.; McDowell, E.; Ebert, B. L.;
Gozo, M.; Cuker, A.; Wernig, G.; Moore, S.; Galinsky, I.; DeAngelo,
D. J.; Clark, J. J.; Lee, S. J.; Golub, T. R.; Wadleigh, M.; Gilliland,
D. G.; Levine, R. L.: MPLW515L is a novel somatic activating mutation
in myelofibrosis with myeloid metaplasia. PLoS Med. 3: e270, 2006.
Note: Electronic Article.

9. Sieff, C. A.; Malleson, P.: Familial myelofibrosis. Arch. Dis.
Child. 55: 888-893, 1980.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Myeloproliferative disease;
Reduced hemopoiesis;
Generalized bone marrow fibrosis;
No hemophagocytosis

MISCELLANEOUS:
Onset first weeks of life

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/10/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 3/27/2008
Victor A. McKusick - updated: 5/10/2005
Victor A. McKusick - updated: 2/24/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 02/07/2014
carol: 1/8/2014
ckniffin: 1/7/2014
carol: 11/14/2012
terry: 11/13/2012
ckniffin: 10/24/2011
wwang: 10/26/2010
ckniffin: 10/25/2010
wwang: 10/14/2009
ckniffin: 9/15/2009
wwang: 6/12/2009
terry: 6/10/2009
carol: 4/7/2008
ckniffin: 3/27/2008
tkritzer: 5/18/2005
tkritzer: 5/16/2005
terry: 5/10/2005
carol: 3/7/1999
terry: 2/24/1999
mimman: 2/8/1996
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

MIM 601977
*RECORD*
*FIELD* NO
601977
*FIELD* TI
#601977 THROMBOCYTHEMIA 2; THCYT2
*FIELD* TX
A number sign (#) is used with this entry because thrombocythemia-2
read more(THCYT2) is caused by heterozygous germline or somatic mutation in the
MPL gene (159530) on chromosome 1p34.

For a general phenotypic description and a discussion of genetic
heterogeneity of thrombocythemia, see THCYT1 (187950).

CLINICAL FEATURES

Ding et al. (2004) reported a 3-generation Japanese family in which 8 of
16 members had thrombocythemia, with a platelet count more than 600 x
109/L. Bone marrow biopsies were normocellular and normoplastic, except
for increased megakaryocytes.

INHERITANCE

The transmission pattern in the family reported by Ding et al. (2004)
was consistent with autosomal dominant inheritance.

MOLECULAR GENETICS

- Germline Mutation in the MPL Gene

In affected members of a Japanese family with autosomal dominant
thrombocythemia, Ding et al. (2004) identified a heterozygous activating
mutation in the MPL gene (159530.0010).

Moliterno et al. (2004) found that approximately 7% of African Americans
are heterozygous for a single nucleotide substitution in the MPL gene,
1238G-T, which results in a lys39-to-asn substitution (K39N;
159530.0009). African Americans with the K39N polymorphism, which the
authors designated MPL Baltimore, had a significantly higher platelet
count than controls without the polymorphism (p less than 0.001) and
reduced platelet protein MPL expression. Moliterno et al. (2004)
concluded that K39N represents a functional MPL polymorphism and is
associated with altered protein expression of the thrombopoietin
receptor and a clinical phenotype of thrombocytosis. Although DNA was
isolated from platelets or peripheral blood from most individuals in the
study, K39N was also present in DNA obtained from buccal smears from 2
of the patients available for study.

- Somatic Mutation in the MPL Gene

Pardanani et al. (2006) identified a somatic mutation in the MPL gene
(W515L; 159530.0011) in 4 unrelated patients with thrombocythemia.

*FIELD* RF
1. Ding, J.; Komatsu, H.; Wakita, A.; Kato-Uranishi, M.; Ito, M.;
Satoh, A.; Tsuboi, K.; Nitta, M.; Miyazaki, H.; Iida, S.; Ueda, R.
: Familial essential thrombocythemia associated with a dominant-positive
activating mutation of the c-MPL gene, which encodes for the receptor
for thrombopoietin. Blood 103: 4198-4200, 2004.

2. Moliterno, A. R.; Williams, D. M.; Gutierrez-Alamillo, L. I.; Salvatori,
R.; Ingersoll, R. G.; Spivak, J. L.: Mpl Baltimore: a thrombopoietin
receptor polymorphism associated with thrombocytosis. Proc. Nat.
Acad. Sci. 101: 11444-11447, 2004.

3. Pardanani, A. D.; Levine, R. L.; Lasho, T.; Pikman, Y.; Mesa, R.
A.; Wadleigh, M.; Steensma, D. P.; Elliott, M. A.; Wolanskyj, A.
P.; Hogan, W. J.; McClure, R. F.; Litzow, M. R.; Gilliland, D. G.;
Tefferi, A.: MPL515 mutations in myeloproliferative and other myeloid
disorders: a study of 1182 patients. Blood 108: 3472-3476, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Somatic mutation

HEMATOLOGY:
Thrombocythemia;
Increased megakaryocytes in bone marrow

MISCELLANEOUS:
Germline or somatic mutations may cause the disorder

MOLECULAR BASIS:
Caused by mutation in the myeloproliferative leukemia virus oncogene
(MPL, 159530.0009)

*FIELD* CN
Cassandra L. Kniffin - revised: 3/8/2012

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/01/2012
ckniffin: 3/8/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 3/8/2012

*FIELD* CD
Victor A. McKusick: 9/5/1997

*FIELD* ED
carol: 03/09/2012
ckniffin: 3/8/2012
jenny: 9/5/1997

MIM 604498
*RECORD*
*FIELD* NO
604498
*FIELD* TI
#604498 AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL; CAMT
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morecongenital amegakaryocytic thrombocytopenia (CAMT) can be caused by
homozygous or compound heterozygous mutation in the myeloproliferative
leukemia virus oncogene (MPL; 159530) on chromosome 1p34.

DESCRIPTION

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder
expressed in infancy and characterized by isolated thrombocytopenia and
megakaryocytopenia with no physical anomalies (Muraoka et al., 1997).

King et al. (2005) proposed a new classification of CAMT based on the
course and outcome of the disease, as exemplified by 20 patients: CAMT
type I (11 patients) was characterized by early onset of severe
pancytopenia, decreased bone marrow activity, and very low platelet
counts. CAMT type II (9 patients) was somewhat milder and characterized
by transient increases of platelet counts up to nearly normal values
during the first year of life and an onset of bone marrow failure at age
3 or later.

CLINICAL FEATURES

Muraoka et al. (1997) found that a patient with CAMT had a defective
response to thrombopoietin (TPO; 600044) in megakaryocyte-colony
formation, decreased numbers of erythroid and myelocytic progenitors in
clonal cultures, a lack of MPL mRNA in bone marrow mononuclear cells,
and an elevated serum level of TPO. Ihara et al. (1999) provided a
follow-up of the patient reported by Muraoka et al. (1997). She was a
10-year-old girl born to nonconsanguineous Japanese parents. She
appeared to be healthy at birth; however, laboratory data showed an
isolated thrombocytopenia in the peripheral blood and an absence of
megakaryocytes in the bone marrow. The platelet count was 2,000 in the
bone marrow. Magnetic resonance imaging (MRI) of the brain showed a
hypoplastic cerebellar vermis with a communication between the fourth
ventricle and the cisterna magna. Despite this malformation, the child
exhibited normal neurologic development and normal physical and
developmental growth. The karyotype of the lymphocytes was normal. In
addition to thrombocytopenia, white blood cell and red blood cell counts
gradually decreased with age. At the age of 6 years, the serum TPO level
was significantly higher than that in healthy controls.

Ballmaier et al. (2001) analyzed 9 patients with congenital
amegakaryocytic thrombocytopenia for defects in TPO production and
reactivity. High levels of TPO were found in the sera of all patients;
however, platelets and hematopoietic progenitor cells of patients with
the disorder showed no reactivity to TPO, as measured by testing
TPO-synergism to adenosine diphosphate in platelet activation or by
megakaryocyte colony assays. Flow cytometry revealed absent surface
expression of the TPO receptor MPL in 3 of 3 patients analyzed. Sequence
analysis of the MPL gene in 8 of the patients revealed point mutations
in all.

Ballmaier et al. (2001) stated that a retrospective comparison of
clinical data from 18 patients with CAMT from different German clinics
resulted in a division into 2 different groups. Group I patients
(approximately 60%) presented with a more severe form of CAMT with an
early development from isolated thrombocytopenia into pancytopenia.
Group II patients demonstrated a transient increase of platelet counts
during the first year of life and a later development of pancytopenia.

King et al. (2005) studied 20 children with CAMT, including 7 previously
analyzed for TPO reactivity and MPL mutations by Ballmaier et al.
(2001). Six (30%) of the 20 children died. Prognostic factors for
survival were severity of thrombocytopenia and pancytopenia during the
course of the disease; there was no correlation between outcome and
initial platelet count.

Pemberton et al. (2006) reported a British boy with CAMT confirmed by
genetic analysis. He presented with thrombocytopenia in infancy,
developed neutropenia at age 1 year, and progressed to full pancytopenia
by age 5 years. Bone marrow biopsy was hypoplastic with markedly
decreased numbers of megakaryocytes and no dysplasia. He underwent a
donor hematopoietic stem cell transplant and remained well with stable
engraftment at 1-year follow-up.

MOLECULAR GENETICS

The considerable similarities between human CAMT and murine mpl
deficiency prompted Ihara et al. (1999) to analyze the MPL gene in a
patient with CAMT reported by Muraoka et al. (1997). MPL was not
detected in her bone mononuclear cells by RT-PCR or by Northern blot
analysis. By DNA studies, Ihara et al. (1999) detected compound
heterozygosity for 2 mutations of the MPL gene: a gln186-to-ter
substitution in exon 4 (159530.0001), and a single nucleotide deletion
in exon 10 (159530.0002).

GENOTYPE/PHENOTYPE CORRELATIONS

King et al. (2005) found that patients with the more severe CAMT type I
phenotype carried nonsense MPL mutations predicted to cause a complete
loss of the TPO receptor, whereas those with the milder type II
phenotype carried missense mutations in the MPL gene affecting the
extracellular domain of the TPO receptor. King et al. (2005) suggested
that the latter mutations likely result in proteins with residual
function and a milder phenotype.

ANIMAL MODEL

Animal studies showed that a deficiency of the Mpl gene results in
amegakaryocytic thrombocytopenia, decreased numbers of hematopoietic
progenitors, and increased concentrations of circulating TPO with no
physical or developmental abnormalities. Gurney et al. (1994) found that
Mpl-null mice had an 85% decrease in the number of platelets and
megakaryocytes but had normal amounts of other hematopoietic cell types.
These mice also had increased concentrations of circulating TPO. These
results showed that MPL specifically regulates megakaryocytopoiesis and
thrombopoiesis through activation by its ligand TPO.

*FIELD* RF
1. Ballmaier, M.; Germeshausen, M.; Schulze, H.; Cherkaoui, K.; Lang,
S.; Gaudig, A.; Krukemeier, S.; Eilers, M.; Straub, G.; Welte, K.
: c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 97:
139-146, 2001.

2. Gurney, A. L.; Carver-Moore, K.; de Sauvage, F. J.; Moore, M. W.
: Thrombocytopenia in c-mpl-deficient mice. Science 265: 1445-1447,
1994.

3. Ihara, K.; Ishii, E.; Eguchi, M.; Takada, H.; Suminoe, A.; Good,
R. A.; Hara, T.: Identification of mutations in the c-mpl gene in
congenital amegakaryocytic thrombocytopenia. Proc. Nat. Acad. Sci. 96:
3132-3136, 1999.

4. King, S.; Germeshausen, M.; Strauss, G.; Welte, K.; Ballmaier,
M.: Congenital amegakaryocytic thrombocytopenia: a retrospective
clinical analysis of 20 patients. Brit. J. Haemat. 131: 636-644,
2005.

5. Muraoka, K.; Ishii, E.; Tsuji, K.; Yamamoto, S.; Yamaguchi, H.;
Hara, T.; Koga, H.; Nakahata, T.; Miyazaki, S.: Defective response
to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow
cells in congenital amegakaryocytic thrombocytopenia. Brit. J. Haemat. 96:
287-292, 1997.

6. Pemberton, L. C.; Levett, D.; Skinner, R.; Hall, A. G.; Hanley,
J. P.: Novel mutations in a child with congenital amegakaryocytic
thrombocytopenia. (Letter) Brit. J. Haemat. 135: 742-746, 2006.

*FIELD* CS
INHERITANCE:
Autosomal recessive

SKELETAL:
[Limbs];
Normal radii

NEUROLOGIC:
[Central nervous system];
Hypoplastic cerebellar vermis

HEMATOLOGY:
Severe thrombocytopenia (birth);
Pancytopenia (childhood);
Megakaryocytopenia;
Elevated serum thrombopoietin (TPO)

MOLECULAR BASIS:
Caused by mutations in myeloproliferative leukemia virus oncogene
(MPL, 159530.0001)

*FIELD* CD
Kelly A. Przylepa: 10/6/2004

*FIELD* ED
joanna: 10/06/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 3/11/2009
Marla J. F. O'Neill - updated: 3/30/2006
Victor A. McKusick - updated: 8/28/2001

*FIELD* CD
Victor A. McKusick: 2/4/2000

*FIELD* ED
carol: 04/24/2012
terry: 3/26/2012
wwang: 3/18/2009
ckniffin: 3/11/2009
ckniffin: 2/5/2009
wwang: 3/31/2006
terry: 3/30/2006
mcapotos: 8/28/2001
carol: 10/4/2000
mgross: 2/4/2000