RBCC Red Blood Cell Collection

BMPR2 (PPH1) [Confidence: low (only semi-automatic identification from reviews)]
Bone morphogenetic protein receptor type-2; BMP type-2 receptor; BMPR-2; 2.7.11.30 (Bone morphogenetic protein receptor type II; BMP type II receptor; BMPR-II; Flags: Precursor)

UniProt Q13873
ID BMPR2_HUMAN Reviewed; 1038 AA.
AC Q13873; Q16569; Q4ZG08; Q53SA5; Q585T8;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2000, sequence version 2.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Bone morphogenetic protein receptor type-2;
DE Short=BMP type-2 receptor;
DE Short=BMPR-2;
DE EC=2.7.11.30;
DE AltName: Full=Bone morphogenetic protein receptor type II;
DE Short=BMP type II receptor;
DE Short=BMPR-II;
DE Flags: Precursor;
GN Name=BMPR2; Synonyms=PPH1;
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].
RC TISSUE=Substantia nigra;
RX PubMed=7644468; DOI=10.1073/pnas.92.17.7632;
RA Rosenzweig B.L., Imamura T., Okadome T., Cox G.N., Yamashita H.,
RA ten Dijke P., Heldin C., Miyazono K.;
RT "Cloning and characterization of a human type II receptor for bone
RT morphogenetic proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7632-7636(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skin fibroblast;
RX PubMed=7673243; DOI=10.1074/jbc.270.38.22522;
RA Nohno T., Ishikawa T., Saito T., Hosokawa K., Noji S., Wosing D.H.,
RA Rosenbaum J.S.;
RT "Identification of a human type II receptor for bone morphogenetic
RT protein-4 that forms differential heteromeric complexes with bone
RT morphogenetic protein type I receptors.";
RL J. Biol. Chem. 270:22522-22526(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7890683; DOI=10.1074/jbc.270.10.5625;
RA Kawabata M., Chytil A., Moses H.L.;
RT "Cloning of a novel type II serine/threonine kinase receptor through
RT interaction with the type I transforming growth factor-beta
RT receptor.";
RL J. Biol. Chem. 270:5625-5630(1995).
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-586, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-379, AND MASS
RP 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 [8]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 189-517 IN COMPLEX WITH ADP.
RG Structural genomics consortium (SGC);
RT "Crystal structure of the BMPR2 kinase domain.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [9]
RP VARIANTS PPH1 GLN-491 AND TRP-491.
RX PubMed=10903931; DOI=10.1086/303059;
RA Deng Z., Morse J.H., Slager S.L., Cuervo N., Moore K.J., Venetos G.,
RA Kalachikov S., Cayanis E., Fischer S.G., Barst R.J., Hodge S.E.,
RA Knowles J.A.;
RT "Familial primary pulmonary hypertension (gene PPH1) is caused by
RT mutations in the bone morphogenetic protein receptor-II gene.";
RL Am. J. Hum. Genet. 67:737-744(2000).
RN [10]
RP VARIANTS PPH1 TYR-60; TYR-117 AND ARG-483.
RX PubMed=11015450; DOI=10.1136/jmg.37.10.741;
RA Thomson J.R., Machado R.D., Pauciulo M.W., Morgan N.V., Humbert M.,
RA Elliott G.C., Ward K., Yacoub M., Mikhail G., Rogers P., Newman J.H.,
RA Wheeler L., Higenbottam T., Gibbs J.S.R., Egan J., Crozier A.,
RA Peacock A., Allcock R., Corris P., Loyd J.E., Trembath R.C.,
RA Nichols W.C.;
RT "Sporadic primary pulmonary hypertension is associated with germline
RT mutations of the gene encoding BMPR-II, a receptor member of the TGF-
RT beta family.";
RL J. Med. Genet. 37:741-745(2000).
RN [11]
RP VARIANTS PPH1 TRP-118; TYR-347 AND GLY-485.
RX PubMed=10973254; DOI=10.1038/79226;
RA Lane K.B., Machado R.D., Pauciulo M.W., Thomson J.R.,
RA Phillips J.A. III, Loyd J.E., Nichols W.C., Trembath R.C., Aldred M.,
RA Brannon C.A., Conneally P.M., Foroud T., Fretwell N., Gaddipati R.,
RA Koller D., Loyd E.J., Morgan N.V., Newman J.H., Prince M.A.,
RA Vilarino Gueell C., Wheeler L.;
RT "Heterozygous germline mutations in BMPR2, encoding a TGF-beta
RT receptor, cause familial primary pulmonary hypertension.";
RL Nat. Genet. 26:81-84(2000).
RN [12]
RP VARIANTS PPH1 ARG-123; SER-123; ARG-420 AND THR-512, VARIANT ASP-224,
RP AND CHARACTERIZATION OF VARIANT PPH1 GLY-485.
RX PubMed=11115378; DOI=10.1086/316947;
RA Machado R.D., Pauciulo M.W., Thomson J.R., Lane K.B., Morgan N.V.,
RA Wheeler L., Phillips J.A. III, Newman J.H., Williams D., Galie N.,
RA Manes A., McNeil K., Yacoub M., Mikhail G., Rogers P., Corris P.,
RA Humbert M., Donnai D., Martensson G., Tranebjaerg L., Loyd J.E.,
RA Trembath R.C., Nichols W.C.;
RT "BMPR2 haploinsufficiency as the inherited molecular mechanism for
RT primary pulmonary hypertension.";
RL Am. J. Hum. Genet. 68:92-102(2001).
RN [13]
RP VARIANTS PPH1 HIS-82; ASP-182 AND ARG-483.
RX PubMed=12358323; DOI=10.1183/09031936.02.01762002;
RA Humbert M., Deng Z., Simonneau G., Barst R.J., Sitbon O., Wolf M.,
RA Cuervo N., Moore K.J., Hodge S.E., Knowles J.A., Morse J.H.;
RT "BMPR2 germline mutations in pulmonary hypertension associated with
RT fenfluramine derivatives.";
RL Eur. Respir. J. 20:518-523(2002).
RN [14]
RP INVOLVEMENT IN PVOD.
RX PubMed=12446270; DOI=10.1164/rccm.200208-861OC;
RA Runo J.R., Vnencak-Jones C.L., Prince M., Loyd J.E., Wheeler L.,
RA Robbins I.M., Lane K.B., Newman J.H., Johnson J., Nichols W.C.,
RA Phillips J.A. III;
RT "Pulmonary veno-occlusive disease caused by an inherited mutation in
RT bone morphogenetic protein receptor II.";
RL Am. J. Respir. Crit. Care Med. 167:889-894(2003).
RN [15]
RP VARIANT PPH1 PRO-899, AND CHARACTERIZATION OF VARIANT PPH1 PRO-899.
RX PubMed=15965979; DOI=10.1002/humu.20200;
RA Sankelo M., Flanagan J.A., Machado R., Harrison R., Rudarakanchana N.,
RA Morrell N., Dixon M., Halme M., Puolijoki H., Kere J., Elomaa O.,
RA Kupari M., Raeisaenen-Sokolowski A., Trembath R.C., Laitinen T.;
RT "BMPR2 mutations have short lifetime expectancy in primary pulmonary
RT hypertension.";
RL Hum. Mutat. 26:119-124(2005).
RN [16]
RP INVOLVEMENT IN PVOD.
RX PubMed=16429395; DOI=10.1002/humu.20285;
RA Machado R.D., Aldred M.A., James V., Harrison R.E., Patel B.,
RA Schwalbe E.C., Gruenig E., Janssen B., Koehler R., Seeger W.,
RA Eickelberg O., Olschewski H., Elliott C.G., Glissmeyer E.,
RA Carlquist J., Kim M., Torbicki A., Fijalkowska A., Szewczyk G.,
RA Parma J., Abramowicz M.J., Galie N., Morisaki H., Kyotani S.,
RA Nakanishi N., Morisaki T., Humbert M., Simonneau G., Sitbon O.,
RA Soubrier F., Coulet F., Morrell N.W., Trembath R.C.;
RT "Mutations of the TGF-beta type II receptor BMPR2 in pulmonary
RT arterial hypertension.";
RL Hum. Mutat. 27:121-132(2006).
RN [17]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-775.
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).
CC -!- FUNCTION: On ligand binding, forms a receptor complex consisting
CC of two type II and two type I transmembrane serine/threonine
CC kinases. Type II receptors phosphorylate and activate type I
CC receptors which autophosphorylate, then bind and activate SMAD
CC transcriptional regulators. Binds to BMP-7, BMP-2 and, less
CC efficiently, BMP-4. Binding is weak but enhanced by the presence
CC of type I receptors for BMPs.
CC -!- CATALYTIC ACTIVITY: ATP + [receptor-protein] = ADP + [receptor-
CC protein] phosphate.
CC -!- COFACTOR: Magnesium or manganese (By similarity).
CC -!- INTERACTION:
CC P08607:C4bpa (xeno); NbExp=3; IntAct=EBI-527196, EBI-527325;
CC P43026:GDF5; NbExp=4; IntAct=EBI-527196, EBI-8571476;
CC P68404:Prkcb (xeno); NbExp=4; IntAct=EBI-527196, EBI-397048;
CC Q13976:PRKG1; NbExp=2; IntAct=EBI-527196, EBI-3952014;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- TISSUE SPECIFICITY: Highly expressed in heart and liver.
CC -!- DISEASE: Pulmonary hypertension, primary, 1 (PPH1) [MIM:178600]: A
CC rare disorder characterized by plexiform lesions of proliferating
CC endothelial cells in pulmonary arterioles. The lesions lead to
CC elevated pulmonary arterial pression, right ventricular failure,
CC and death. The disease can occur from infancy throughout life and
CC it has a mean age at onset of 36 years. Penetrance is reduced.
CC Although familial pulmonary hypertension is rare, cases secondary
CC to known etiologies are more common and include those associated
CC with the appetite-suppressant drugs. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Pulmonary venoocclusive disease (PVOD) [MIM:265450]: Rare
CC form of pulmonary hypertension in which the vascular changes
CC originate in the small pulmonary veins and venules. The
CC pathogenesis is unknown and any link with PPH1 has been
CC speculative. The finding of PVOD associated with a BMPR2 mutation
CC reveals a possible pathogenetic connection with PPH1. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. TGFB receptor subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BMPR2";
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DR EMBL; Z48923; CAA88759.1; -; mRNA.
DR EMBL; D50516; BAA09094.1; -; mRNA.
DR EMBL; U20165; AAC50105.1; -; mRNA.
DR EMBL; AC009960; AAX76517.1; -; Genomic_DNA.
DR EMBL; AC073410; AAX88941.1; -; Genomic_DNA.
DR EMBL; AC064836; AAY24146.1; -; Genomic_DNA.
DR EMBL; BC052985; AAH52985.1; -; mRNA.
DR PIR; I38935; I38935.
DR RefSeq; NP_001195.2; NM_001204.6.
DR UniGene; Hs.471119; -.
DR PDB; 2HLQ; X-ray; 1.45 A; A=33-131.
DR PDB; 3G2F; X-ray; 2.35 A; A/B=189-517.
DR PDBsum; 2HLQ; -.
DR PDBsum; 3G2F; -.
DR ProteinModelPortal; Q13873; -.
DR SMR; Q13873; 33-131, 197-510.
DR DIP; DIP-5794N; -.
DR IntAct; Q13873; 33.
DR MINT; MINT-124272; -.
DR STRING; 9606.ENSP00000363708; -.
DR BindingDB; Q13873; -.
DR ChEMBL; CHEMBL5467; -.
DR GuidetoPHARMACOLOGY; 1794; -.
DR PhosphoSite; Q13873; -.
DR DMDM; 12643724; -.
DR PaxDb; Q13873; -.
DR PRIDE; Q13873; -.
DR DNASU; 659; -.
DR Ensembl; ENST00000374580; ENSP00000363708; ENSG00000204217.
DR GeneID; 659; -.
DR KEGG; hsa:659; -.
DR UCSC; uc002uzf.4; human.
DR CTD; 659; -.
DR GeneCards; GC02P203205; -.
DR HGNC; HGNC:1078; BMPR2.
DR HPA; HPA017385; -.
DR MIM; 178600; phenotype.
DR MIM; 265450; phenotype.
DR MIM; 600799; gene.
DR neXtProt; NX_Q13873; -.
DR Orphanet; 275777; Heritable pulmonary arterial hypertension.
DR Orphanet; 275766; Idiopathic pulmonary arterial hypertension.
DR Orphanet; 31837; Pulmonary venoocclusive disease.
DR PharmGKB; PA25388; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000043088; -.
DR HOVERGEN; HBG050705; -.
DR InParanoid; Q13873; -.
DR KO; K04671; -.
DR OMA; DHYKPAI; -.
DR OrthoDB; EOG7JHM5B; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q13873; -.
DR ChiTaRS; BMPR2; human.
DR EvolutionaryTrace; Q13873; -.
DR GeneWiki; BMPR2; -.
DR GenomeRNAi; 659; -.
DR NextBio; 2680; -.
DR PRO; PR:Q13873; -.
DR ArrayExpress; Q13873; -.
DR Bgee; Q13873; -.
DR CleanEx; HS_BMPR2; -.
DR Genevestigator; Q13873; -.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0016362; F:activin receptor activity, type II; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005024; F:transforming growth factor beta-activated receptor activity; IEA:InterPro.
DR GO; GO:0009952; P:anterior/posterior pattern specification; ISS:BHF-UCL.
DR GO; GO:0060840; P:artery development; ISS:BHF-UCL.
DR GO; GO:0001974; P:blood vessel remodeling; ISS:BHF-UCL.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0009267; P:cellular response to starvation; IEP:BHF-UCL.
DR GO; GO:0048286; P:lung alveolus development; ISS:BHF-UCL.
DR GO; GO:0001946; P:lymphangiogenesis; ISS:BHF-UCL.
DR GO; GO:0060836; P:lymphatic endothelial cell differentiation; ISS:BHF-UCL.
DR GO; GO:0001707; P:mesoderm formation; ISS:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:2000279; P:negative regulation of DNA biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IMP:BHF-UCL.
DR GO; GO:0045906; P:negative regulation of vasoconstriction; ISS:BHF-UCL.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IMP:UniProtKB.
DR GO; GO:0030501; P:positive regulation of bone mineralization; IMP:BHF-UCL.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IMP:UniProtKB.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0014916; P:regulation of lung blood pressure; IMP:BHF-UCL.
DR GO; GO:0061298; P:retina vasculature development in camera-type eye; ISS:BHF-UCL.
DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; IMP:BHF-UCL.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0060841; P:venous blood vessel development; ISS:BHF-UCL.
DR InterPro; IPR000472; Activin_rcpt.
DR InterPro; IPR015770; BMPRII.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR PANTHER; PTHR23255:SF12; PTHR23255:SF12; 1.
DR Pfam; PF01064; Activin_recp; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Complete proteome; Disease mutation;
KW Disulfide bond; Glycoprotein; Kinase; Magnesium; Manganese; Membrane;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Serine/threonine-protein kinase; Signal;
KW Transferase; Transmembrane; Transmembrane helix.
FT SIGNAL 1 26 Potential.
FT CHAIN 27 1038 Bone morphogenetic protein receptor type-
FT 2.
FT /FTId=PRO_0000024415.
FT TOPO_DOM 27 150 Extracellular (Potential).
FT TRANSMEM 151 171 Helical; (Potential).
FT TOPO_DOM 172 1038 Cytoplasmic (Potential).
FT DOMAIN 203 504 Protein kinase.
FT NP_BIND 209 217 ATP.
FT NP_BIND 280 282 ATP.
FT NP_BIND 337 338 ATP.
FT COMPBIAS 547 550 Poly-Ser.
FT COMPBIAS 610 618 Poly-Thr.
FT COMPBIAS 901 908 Poly-Asn.
FT ACT_SITE 333 333 Proton acceptor (By similarity).
FT BINDING 230 230 ATP.
FT BINDING 351 351 ATP.
FT MOD_RES 379 379 Phosphothreonine.
FT MOD_RES 586 586 Phosphoserine.
FT CARBOHYD 55 55 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 110 110 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 126 126 N-linked (GlcNAc...) (Potential).
FT DISULFID 34 66 By similarity.
FT DISULFID 94 117 By similarity.
FT VARIANT 60 60 C -> Y (in PPH1).
FT /FTId=VAR_013670.
FT VARIANT 82 82 Q -> H (in PPH1).
FT /FTId=VAR_033109.
FT VARIANT 117 117 C -> Y (in PPH1).
FT /FTId=VAR_013671.
FT VARIANT 118 118 C -> W (in PPH1).
FT /FTId=VAR_013672.
FT VARIANT 123 123 C -> R (in PPH1).
FT /FTId=VAR_013673.
FT VARIANT 123 123 C -> S (in PPH1).
FT /FTId=VAR_013674.
FT VARIANT 182 182 G -> D (in PPH1).
FT /FTId=VAR_033110.
FT VARIANT 224 224 E -> D.
FT /FTId=VAR_013675.
FT VARIANT 347 347 C -> Y (in PPH1).
FT /FTId=VAR_013676.
FT VARIANT 420 420 C -> R (in PPH1).
FT /FTId=VAR_013677.
FT VARIANT 483 483 C -> R (in PPH1; sporadic).
FT /FTId=VAR_013678.
FT VARIANT 485 485 D -> G (in PPH1; complete loss of
FT function).
FT /FTId=VAR_013679.
FT VARIANT 491 491 R -> Q (in PPH1; sporadic).
FT /FTId=VAR_013680.
FT VARIANT 491 491 R -> W (in PPH1).
FT /FTId=VAR_013681.
FT VARIANT 512 512 K -> T (in PPH1).
FT /FTId=VAR_013682.
FT VARIANT 519 519 N -> K (in PPH1).
FT /FTId=VAR_013683.
FT VARIANT 775 775 S -> N (in dbSNP:rs2228545).
FT /FTId=VAR_019996.
FT VARIANT 899 899 R -> P (in PPH1; leads to constitutive
FT activation of the MAPK14 pathway;
FT dbSNP:rs137852752).
FT /FTId=VAR_033111.
FT CONFLICT 828 828 G -> R (in Ref. 1; CAA88759).
FT STRAND 33 35
FT TURN 42 47
FT HELIX 48 50
FT TURN 53 56
FT STRAND 57 59
FT STRAND 66 73
FT STRAND 76 84
FT STRAND 90 92
FT TURN 105 109
FT STRAND 113 118
FT HELIX 123 125
FT STRAND 202 211
FT STRAND 213 222
FT STRAND 225 233
FT HELIX 234 236
FT HELIX 237 247
FT STRAND 260 267
FT STRAND 273 279
FT HELIX 287 293
FT HELIX 298 316
FT HELIX 322 324
FT STRAND 338 341
FT STRAND 347 349
FT STRAND 359 362
FT HELIX 380 382
FT HELIX 385 388
FT HELIX 394 396
FT HELIX 397 417
FT HELIX 421 423
FT HELIX 437 440
FT HELIX 446 453
FT HELIX 471 483
FT HELIX 488 490
FT HELIX 494 506
SQ SEQUENCE 1038 AA; 115201 MW; 1389923CE574B913 CRC64;
MTSSLQRPWR VPWLPWTILL VSTAAASQNQ ERLCAFKDPY QQDLGIGESR ISHENGTILC
SKGSTCYGLW EKSKGDINLV KQGCWSHIGD PQECHYEECV VTTTPPSIQN GTYRFCCCST
DLCNVNFTEN FPPPDTTPLS PPHSFNRDET IIIALASVSV LAVLIVALCF GYRMLTGDRK
QGLHSMNMME AAASEPSLDL DNLKLLELIG RGRYGAVYKG SLDERPVAVK VFSFANRQNF
INEKNIYRVP LMEHDNIARF IVGDERVTAD GRMEYLLVME YYPNGSLCKY LSLHTSDWVS
SCRLAHSVTR GLAYLHTELP RGDHYKPAIS HRDLNSRNVL VKNDGTCVIS DFGLSMRLTG
NRLVRPGEED NAAISEVGTI RYMAPEVLEG AVNLRDCESA LKQVDMYALG LIYWEIFMRC
TDLFPGESVP EYQMAFQTEV GNHPTFEDMQ VLVSREKQRP KFPEAWKENS LAVRSLKETI
EDCWDQDAEA RLTAQCAEER MAELMMIWER NKSVSPTVNP MSTAMQNERN LSHNRRVPKI
GPYPDYSSSS YIEDSIHHTD SIVKNISSEH SMSSTPLTIG EKNRNSINYE RQQAQARIPS
PETSVTSLST NTTTTNTTGL TPSTGMTTIS EMPYPDETNL HTTNVAQSIG PTPVCLQLTE
EDLETNKLDP KEVDKNLKES SDENLMEHSL KQFSGPDPLS STSSSLLYPL IKLAVEATGQ
QDFTQTANGQ ACLIPDVLPT QIYPLPKQQN LPKRPTSLPL NTKNSTKEPR LKFGSKHKSN
LKQVETGVAK MNTINAAEPH VVTVTMNGVA GRNHSVNSHA ATTQYANGTV LSGQTTNIVT
HRAQEMLQNQ FIGEDTRLNI NSSPDEHEPL LRREQQAGHD EGVLDRLVDR RERPLEGGRT
NSNNNNSNPC SEQDVLAQGV PSTAADPGPS KPRRAQRPNS LDLSATNVLD GSSIQIGEST
QDGKSGSGEK IKKRVKTPYS LKRWRPSTWV ISTESLDCEV NNNGSNRAVH SKSSTAVYLA
EGGTATTMVS KDIGMNCL
//

MIM 178600
*RECORD*
*FIELD* NO
178600
*FIELD* TI
#178600 PULMONARY HYPERTENSION, PRIMARY, 1; PPH1
;;PHT;;
PULMONARY ARTERIAL HYPERTENSION; PAH
read morePULMONARY HYPERTENSION, PRIMARY, DEXFENFLURAMINE-ASSOCIATED, INCLUDED;;
PULMONARY HYPERTENSION, PRIMARY, FENFLURAMINE-ASSOCIATED, INCLUDED;;
PULMONARY HYPERTENSION, PRIMARY, 1, WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA,
INCLUDED;;
PPH1 WITH HHT, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
primary pulmonary hypertension-1 (PPH1) is caused by heterozygous
mutation in the BMPR2 gene (600799) on chromosome 2q33.

DESCRIPTION

Primary pulmonary arterial hypertension is a rare, often fatal,
progressive vascular lung disease characterized by increased pulmonary
vascular resistance and sustained elevation of mean pulmonary arterial
pressure, leading to right ventricular hypertrophy and right heart
failure. Pathologic features include a narrowing and thickening of small
pulmonary vessels and plexiform lesions. There is pulmonary vascular
remodeling of all layers of pulmonary arterial vessels: intimal
thickening, smooth muscle cell hypertrophy or hyperplasia, adventitial
fibrosis, and occluded vessels by in situ thrombosis (summary by Machado
et al., 2009 and Han et al., 2013).

Heterozygous mutations in the BMPR2 gene are found in nearly 70% of
families with heritable PPH and in 25% of patients with sporadic
disease. The disease is more common in women (female:male ratio of
1.7:1). However, the penetrance of PPH1 is incomplete: only about 10 to
20% of individuals with BMPR2 mutations develop the disease during their
lifetime, suggesting that development of the disorder is triggered by
other genetic or environmental factors. Patients with PPH1 are less
likely to respond to acute vasodilater testing and are unlikely to
benefit from treatment with calcium channel blockade (summary by Machado
et al., 2009 and Han et al., 2013).

- Genetic Heterogeneity of Primary Pulmonary Hypertension

PPH2 (615342) is caused by mutation in the SMAD9 gene (603295) on
chromosome 13q12; PPH3 (615343) is caused by mutation in the CAV1 gene
(601047) on chromosome 7q31; and PPH4 (615344) is caused by mutation in
the KCNK3 gene (603220) on chromosome 2p24.

See 265400 for a possible autosomal recessive form of PPH.

Primary pulmonary hypertension may also be found in association with
hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300), caused by
mutation in the ENG gene (131195), and HHT2 (600376), caused by mutation
in the ACVRL1 (ALK1) gene (601284).

CLINICAL FEATURES

Melmon and Braunwald (1963) observed 2 proved cases and 3 presumptive
cases of primary pulmonary hypertension (PPH) in 3 generations of a
family. Parry and Verel (1966) described the disorder in a mother and
her 2 daughters and referred to at least 2 other reports of 2
generations being affected. Kingdon et al. (1966) described the
condition in brother and sister and their father.

Morse et al. (1992) described a kindred in which 7 members had primary
pulmonary hypertension and 2 others had this probable diagnosis. The
proband was an 11-year-old girl who had an affected 8-year-old sister.
The paternal grandmother died at the age of 21 in severe right heart
failure, 3 days after delivering her third child. Three other remarkable
families were reported. In affected members of a family with pulmonary
hypertension, Inglesby et al. (1973) found elevated levels of
antiplasmin (613168).

- Pulmonary Hypertension with Hereditary Hemorrhagic Telangiectasia

Rigelsky et al. (2008) reported a woman diagnosed with pulmonary
hypertension at age 24 years. She developed massive hemoptysis at age
35, prompting the discovery of multiple pulmonary arteriovenous
malformations consistent with a diagnosis of hereditary hemorrhagic
telangiectasia. She also had recurrent epistaxis and nasal
telangiectasia. The patient was adopted, and there was no family history
available. Genetic analysis revealed a heterozygous mutation in the
BMPR2 gene (Q433X; 600799.0026). Mutations in the ACVRL1, ENG (131195),
and SMAD4 (600993) genes were excluded. Rigelsky et al. (2008) noted
that, although PAH with HHT had usually only been associated with
mutations in the ACVRL1 gene, their patient was the first report of PAH
and HHT associated with a mutation in the BMPR2 gene. The findings
indicated a common molecular pathogenesis in PAH and HHT, most likely
dysregulated BMP9 (GDF2; 605120) signaling.

CLINICAL MANAGEMENT

Gaine and Rubin (1998) reviewed progress in treatment of PPH. The
prognosis of untreated PPH is poor. Treatment with oral calcium channel
blockers is helpful for a very small percentage of PPH patients, and
oral anticoagulation therapy was standard care at the time of the
report. Treatment with continuous intravenous epoprostenol had been
shown in randomized trials to prolong life and improve clinical
function, but it is complicated (requires a chronic indwelling central
venous catheter) and expensive. Lung transplantation is a final
alternative therapy for patients who do not improve with medical
therapies.

INHERITANCE

Familial PPH is rare and has an incidence of approximately 1 in 100,000
to 1 in 1,000,000. Familial PPH has an autosomal dominant mode of
inheritance, reduced penetrance, affects more females than males, and
exhibits genetic anticipation (Deng et al., 2000; the International PPH
Consortium et al., 2000). Quoting Rich et al. (1987), Rubin (1997)
stated that 'familial primary pulmonary hypertension accounted for 6
percent of the 187 cases in the NIH registry.' Incomplete penetrance and
a 2-5:1 female predilection is evident in the analysis of published
cases. X-linked inheritance is excluded by rare instances of
male-to-male transmission and, in one case, of transmission from
grandfather to grandson through an unaffected son (Newman, 1981).

Loyd et al. (1984) presented compelling evidence of autosomal dominant
inheritance with female preference. They observed 6 deaths from PPH in 2
generations: 4 sisters and 1 daughter of each of 2 of the sisters. In a
survey of 9 of the 13 families with PPH reported from North America,
they found 8 new cases of PPH in 5 of the 9. There was a 2 to 1
female-to-male ratio, but in one instance male-to-male transmission was
observed. In one family, the gene was apparently transmitted from an
affected male through 2 generations of unaffected females to a male who
died of the disease at age 6.

Loyd et al. (1995) found a pattern of autosomal dominant inheritance
with anticipation, a worsening of the disease in successive generations.

MAPPING

Morse et al. (1997) used linkage analysis to map the PPH1 gene to
chromosome 2q31-q32 in 2 ethnically distinct families.

Following a genomewide search using a set of highly polymorphic short
tandem repeat (STR) markers and 19 affected individuals from 6 families,
Nichols et al. (1997) obtained initial evidence for linkage with 2
chromosome 2q markers. They subsequently genotyped patients and all
available family members for 19 additional markers spanning
approximately 40 cM on the long arm of chromosome 2. In this way they
obtained a maximum 2-point lod score of 6.97 at theta = 0.0 with marker
D2S389. Multipoint linkage analysis yielded a maximum lod score of 7.86
with the marker D2S311. Haplotype analysis established a minimum
candidate interval of approximately 25 cM.

- Heterogeneity

Morse et al. (1992) suggested that a familial form of primary pulmonary
hypertension may have a susceptibility factor located within or near the
MHC locus on chromosome 6p.

MOLECULAR GENETICS

Members of the TGF-beta superfamily (see, e.g. 190180), including TGFB,
BMPs, and activin, transduce signals by binding to heteromeric complexes
of type I and II serine/threonine kinase receptors, leading to
transcriptional regulation by phosphorylated Smads (e.g., 601366). The
BMPR2 and ACVRL1 genes encode type II and type I serine/threonine kinase
receptors, respectively. Mutation in the SMAD9 gene (also known as
SMAD8) suggests that downregulation of the downstream TGFB/BMP signaling
pathway may play a role in primary pulmonary hypertension (International
PPH Consortium et al., 2000; Shintani et al., 2009).

The International PPH Consortium et al. (2000) and Deng et al. (2000)
showed that PPH1 is caused by mutations in the BMPR2 gene (600799).
These BMPR2 mutations were found in 7 of 8 families exhibiting linkage
to markers adjacent to BMPR2 by the International PPH Consortium et al.
(2000) and in 9 of 19 of the families exhibiting linkage and/or
haplotype sharing with markers adjacent to BMPR2 by Deng et al. (2000).
Both groups found that the BMPR2 mutations are heterogeneous and include
termination, frameshift, and nonconservative missense changes in amino
acid sequence. By comparison with in vitro studies, the International
PPH Consortium et al. (2000) predicted that the identified BMPR2
mutations would disrupt ligand binding, kinase activity, and heteromeric
dimer formation.

Eddahibi et al. (2001) reported that pulmonary artery smooth muscle
cells (SMCs) from patients with PPH grew faster than those from controls
when stimulated with serum or serotonin, due to increased expression of
5-HTT (182138). Inhibitors of 5-HTT attenuated the growth-stimulatory
effects of serum and serotonin. Expression of 5-HTT was increased in
cultured pulmonary artery SMCs as well as in platelets and lungs from
patients with PPH, where it predominated in the media of thickened
pulmonary arteries and in onion bulb lesions. The L allele variant of
the 5-HTT promoter (182138.0001), which is associated with 5-HTT
overexpression and increased pulmonary artery SMC growth, was present in
homozygous form in 65% of PPH patients but in only 27% of controls (p
less than 0.001). Eddahibi et al. (2001) concluded that 5-HTT activity
plays a key role in the pathogenesis of pulmonary artery SMC
proliferation in PPH and that a 5-HTT polymorphism confers
susceptibility to PPH.

Thomson et al. (2000) analyzed the BMPR2 gene in 50 unrelated patients
with sporadic PPH and identified 11 different heterozygous mutations in
13 of the 50 PPH patients, including 3 missense, 3 nonsense (see, e.g.,
600799.0019), and 5 frameshift mutations. Analysis of parental DNA was
possible in 5 cases and showed 3 occurrences of paternal transmission
and 2 of de novo mutation of the BMPR2 gene. Thomson et al. (2000) noted
that because of low penetrance, in the absence of detailed genealogic
data, familial cases may be overlooked.

Humbert et al. (2002) analyzed the BMPR2 gene in 33 unrelated patients
with sporadic PPH and 2 sisters with PPH, all of whom had taken
fenfluramine derivatives. Three BMPR2 mutations (see, e.g., 600799.0020)
were identified in 3 (9%) of the 33 unrelated patients, and a fourth
mutation (R211X; 600799.0019) was identified in the 2 sisters.
Mutation-positive patients had similar clinical and hemodynamic
characteristics when compared to mutation-negative patients, except for
a shorter duration of exposure to fenfluramine derivatives before
illness (median exposure, 1 month and 4 months, respectively). Humbert
et al. (2002) concluded that BMPR2 mutations may combine with exposure
to fenfluramine derivatives to greatly increase the risk of developing
severe pulmonary arterial hypertension.

In 25 families with PPH and 106 patients with sporadic PPH, all of whom
were negative for mutations in the BMPR2 gene by DHPLC analysis or
direct sequencing, Aldred et al. (2006) performed multiplex
ligation-dependent probe amplification (MLPA) analysis to detect gross
BMPR2 rearrangements. Ten different deletions were identified in 7
families and 6 sporadic cases (see, e.g., 600799.0023-600799.0025). One
patient with familial PPH had histologic features of pulmonary
venoocclusive disease (PVOD; 265450) and was found to have a deletion of
exon 2 of the BMPR2 gene (600799.0023); the exon 2 deletion was also
identified in an unrelated family with PPH and no known evidence of
PVOD. Aldred et al. (2006) noted that 2 large deletions were predicted
to result in null alleles (see 600799.0025), providing support for the
hypothesis that the predominant molecular mechanism for disease
predisposition is haploinsufficiency.

Shintani et al. (2009) identified a heterozygous truncating mutation in
the SMAD9 gene (603295.0001) in a patient with PPH. The mutant protein
resulted in downregulation of the downstream TGFB/BMP signaling pathway.

Phillips et al. (2008) studied SNP genotypes of TGF-beta (190180) in
BMPR2 mutation carriers with pulmonary hypertension and examined the age
of diagnosis and penetrance of the pulmonary hypertension phenotype.
BMPR2 heterozygotes with least active -509 or codon 10 TGFB1 SNPs had
later mean age at diagnosis of familial pulmonary arterial hypertension
(39.5 and 43.2 years, respectively) than those with more active
genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively).
Kaplan-Meier analysis showed that those with less active SNPs had later
age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated
decay-resistant BMPR2 mutations and the least, intermediate, and most
active -509 TGFB1 SNP phenotypes had penetrances of 33%, 72%, and 80%,
respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active SNP
alleles had penetrances of 33%, 72%, and 75% (P = 0.005). Phillips et
al. (2008) concluded that the TGFB1 SNPs studied modulate age at
diagnosis and penetrance of familial pulmonary arterial hypertension in
BMPR2 mutation heterozygotes, likely by affecting TGFB/BMP signaling
imbalance. The authors considered this modulation an example of
synergistic heterozygosity.

- Heterogeneity

Grunig et al. (2004) analyzed the BMPR2 gene in 13 unrelated children
with PPH diagnosed between the ages of 6 months and 13 years and
invasively confirmed, but found no mutations or deletions. Linkage to
chromosomes 2 or 12 could not be confirmed in any of 6 families studied.
Evaluation of 57 members of 6 families revealed that both parents of the
index patient and/or members of both branches had an abnormal pulmonary
artery systolic pressure response to exercise. Grunig et al. (2004)
concluded that PPH in children may have a different genetic background
than in adults, and postulated a recessive mode of inheritance in a
proportion of infantile cases.

- Associations Pending Confirmation

Germain et al. (2013) conducted a genomewide association study based on
2 independent case-control studies for idiopathic and familial PAH
(without BMPR2 mutations), including a total of 625 cases and 1,525
healthy individuals. Germain et al. (2013) detected a significant
association at the CBLN2 locus (600433) mapping to chromosome 18q22.3,
with the risk allele conferring an odds ratio for PAH of 1.97
(1.59-2.45; p = 7.47 x 10(-10)). CBLN2 is expressed in the lung, and its
expression was higher in explanted lungs from individuals with PAH and
in endothelial cells cultured from explanted PAH lungs than in control
samples.

POPULATION GENETICS

In the Finnish population, Sankelo et al. (2005) reported that
prevalence of PPH was 5.8 cases per million and annual incidence was 0.2
to 1.3 cases per million. Detailed molecular analysis of 26 sporadic
patients and 4 familial cases failed to identify a common founder BMPR2
mutation in this genetically homogeneous population, suggesting that
pathogenic BMPR2 mutations are relatively young.

PATHOGENESIS

Recurrent pulmonary microembolization with impaired fibrinolysis had
been postulated but not proved as the basis of this disorder. Herve et
al. (1990) suggested that inherited platelet storage deficiency with a
high level of 5-hydroxytryptamine in plasma can be a cause of 'primary'
pulmonary hypertension. In 3 Caucasian kindreds with familial primary
pulmonary hypertension, Morse et al. (1992) found that each family had 1
affected person with an IgA or IgG immunoglobulin deficiency and a
specific HLA (142800) typing (HLA-DR3, DRw52,DQw2). Some affected
members of a fourth family had autoantibodies and different HLA
associations. The authors suggested a susceptibility factor within or
near the MHC locus.

Plexiform lesions composed of proliferating endothelial cells occur in
20 to 80% of cases of primary pulmonary hypertension. Lee et al. (1998)
studied the question of whether the endothelial cell proliferation in
these lesions in PPH is monoclonal or polyclonal by means of the
methylation pattern of the androgen receptor gene (313700) by PCR, in
proliferating endothelial cells in plexiform lesions from female 4 PPH
patients compared with 4 secondary pulmonary hypertension patients. In
PPH, 17 of 22 lesions (77%) were monoclonal; however, in secondary PH,
all 19 lesions examined were polyclonal. Smooth muscle cell hyperplasia
in 11 pulmonary vessels in PPH and secondary PH was polyclonal in all
but 1 of the examined vessels. The findings of frequent monoclonal
endothelial cell proliferation in PPH suggested that a somatic genetic
alteration similar to that present in neoplastic processes may be
responsible for the pathogenesis of PPH.

Loyd et al. (1988) analyzed the findings in lung specimens from 23
affected members from 13 families. They found marked heterogeneity in
the pathologic lesions within and among families, including frequent
coexistence of thrombotic and plexiform lesions. They concluded that the
proposed existence of 2 pathologic types of primary pulmonary
hypertension, plexogenic and thromboembolic, is probably not valid. They
noted that the lesions found in this disorder are not specific but
represent different manifestations of the same pathologic process.

Loscalzo (2001) noted that a subset of patients with hereditary
hemorrhagic telangiectasia have lung disease that is similar to PPH. The
pathologic features of the blood vessels of these patients consist of
vascular dilatations and arteriovenous fistulas characteristic of HHT
(see 600376), as well as the occlusive arteriopathy of PPH. Loscalzo
(2001) presented a hypothetical model of the role of mutations in the
BMPR2 and ALK1 (ACVRL1; 601284) genes in the development of primary
pulmonary hypertension and PPH with hereditary hemorrhagic
telangiectasia, respectively.

The spectrum of trigger factors and molecular mechanisms leading to
severe pulmonary hypertension and the formation of plexiform lesions is
wide, including both genetic and epigenetic factors. Cool et al. (2003)
suggested that infection with the vasculotropic virus HHV-8, the
etiologic agent of Kaposi sarcoma (148000), may have a pathogenetic role
in primary pulmonary hypertension.

Machado et al. (2003) determined that TCTEL1 (601544), a light chain of
the motor complex dynein, interacted with the cytoplasmic domain of
BMPR2 and was also phosphorylated by BMPR2, a function disrupted by
PPH1-causing mutations within exon 12 (e.g., 600799.0002). BMPR2 and
TCTEL1 colocalized to endothelium and smooth muscle within the media of
pulmonary arterioles, key sites of vascular remodeling in PPH. The
authors proposed that loss of interaction and lack of phosphorylation of
TCTEL1 by BMPR2 may contribute to the pathogenesis of PPH.

Li et al. (2009) demonstrated that PAH is characterized by
overexpression of NOTCH3 (600276) in small pulmonary artery smooth
muscle cells (SMCs) and that the severity of disease in humans and
rodents correlates with the amount of NOTCH3 protein in the lung. Notch3
-/- mice did not develop pulmonary hypertension in response to hypoxic
stimulation, and both pulmonary hypertension and right ventricular
hypertrophy were ameliorated in mice by treatment with DAPT, a
gamma-secretase (see 104311) inhibitor that blocks activation of NOTCH3
in SMCs. The authors demonstrated a mechanistic link from NOTCH3
receptor signaling through the HES5 protein (607348) to SMC
proliferation and a shift to an undifferentiated SMC phenotype. Li et
al. (2009) suggested that the NOTCH3-HES5 signaling pathway is crucial
for the development of PAH.

In pulmonary endothelial cells derived from 2 of 3 PPH1 patients with
BMPR2 mutations, Drake et al. (2011) found loss of miR21 (611020)
induction in response to BMP9 (605120). These cells also showed greater
proliferation compared to controls; overexpression of miR21 induced
growth suppression. However, canonical BMP signaling was only mildly
attenuated in these cells. The findings suggested that disruption of the
noncanonical BMP-mediated pathway resulting in aberrant miR processing
may play an important role in the pathogenesis of PPH.

ANIMAL MODEL

See 178400 for discussion of pulmonary hypertension in cattle at high
altitude.

Noting that vasoactive intestinal peptide (VIP; 192320) had been
reported absent in pulmonary arteries from patients with idiopathic
pulmonary arterial hypertension, Said et al. (2007) generated Vip -/-
mice and examined them for evidence of PAH. Vip -/- mice exhibited
moderate right ventricular (RV) hypertension, RV hypertrophy confirmed
by increased ratio of RV to left ventricle plus septum weight, and an
enlarged, thickened pulmonary artery and smaller branches with increased
muscularization and narrowed lumens compared to wildtype mice. Lung
sections also showed perivascular inflammatory cell infiltrates. There
was no systemic hypertension or arterial hypoxemia to explain the PAH.
The condition was associated with increased mortality. Both the vascular
remodeling and RV remodeling were attenuated after a 4-week treatment
with VIP. Said et al. (2007) concluded that the Vip -/- mouse was not an
exact model of PAH but would be useful for studying molecular mechanisms
of PAH and evaluating potential therapeutic agents.

*FIELD* SA
Hendrix (1974); Rogge et al. (1966); Thompson and McRae (1970)
*FIELD* RF
1. Aldred, M. A.; Vijayakrishnan, J.; James, V.; Soubrier, F.; Gomez-Sanchez,
M. A.; Martensson, G.; Galie, N.; Manes, A.; Corris, P.; Simonneau,
G.; Humbert, M.; Morrell, N. W.; Trembath, R. C.: BMPR2 gene rearrangements
account for a significant proportion of mutations in familial and
idiopathic pulmonary arterial hypertension. (Abstract) Hum. Mutat. 27:
212-213, 2006. Note: Full article online.

2. Cool, C. D.; Rai, P. R.; Yeager, M. E.; Hernandez-Saavedra, D.;
Serls, A. E.; Bull, T. M.; Geraci, M. W.; Brown, K. K.; Routes, J.
M.; Tuder, R. M.; Voelkel, N. F.: Expression of human herpesvirus
8 in primary pulmonary hypertension. New Eng. J. Med. 349: 1113-1122,
2003.

3. Deng, Z.; Morse, J. H.; Slager, S. L.; Cuervo, N.; Moore, K. J.;
Venetos, G.; Kalachikov, S.; Cayanis, E.; Fischer, S. G.; Barst, R.
J.; Hodge, S. E.; Knowles, J. A.: Familial primary pulmonary hypertension
(gene PPH1) is caused by mutations in the bone morphogenetic protein
receptor-II gene. Am. J. Hum. Genet. 67: 737-744, 2000.

4. Drake, K. M.; Zygmunt, D.; Mavrakis, L.; Harbor, P.; Wang, L.;
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in heritable pulmonary arterial hypertension: an important role for
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5. Eddahibi, S.; Humbert, M.; Fadel, E.; Raffestin, B.; Darmon, M.;
Capron, F.; Simonneau, G.; Dartevelle, P.; Hamon, M.; Adnot, S.:
Serotonin transporter overexpression is responsible for pulmonary
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Clin. Invest. 108: 1141-1150, 2001.

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719-725, 1998. Note: Erratum: Lancet 353: 74 only, 1999.

7. Germain, M.; Eyries, M.; Montani, D.; Poirier, O.; Girerd, B.;
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8. Grunig, E.; Koehler, R.; Miltenberger-Miltenyi, G.; Zimmermann,
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9. Han, C.; Hong, K.-H.; Kim, Y. H.; Kim, M.-J.; Song, C.; Kim, M.
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endothelial or smooth muscle cells can predispose mice to pulmonary
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11. Herve, P.; Drouet, L.; Dosquet, C.; Launay, J.-M.; Rain, B.; Simonneau,
G.; Caen, J.; Duroux, P.: Primary pulmonary hypertension in a patient
with a familial platelet storage pool disease: role of serotonin. Am.
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12. Humbert, M.; Deng, Z.; Simonneau, G.; Barst, R. J.; Sitbon, O.;
Wolf, M.; Cuervo, N.; Moore, K. J.; Hodge, S. E.; Knowles, J. A.;
Morse, J. H.: BMPR2 germline mutations in pulmonary hypertension
associated with fenfluramine derivatives. Europ. Resp. J. 20: 518-523,
2002.

13. Inglesby, T. V.; Singer, J. W.; Gordon, D. S.: Abnormal fibrinolysis
in familial pulmonary hypertension. Am. J. Med. 55: 5-14, 1973.

14. International PPH Consortium; Lane, K. B.; Machado, R. D.; Pauciulo,
M. W.; Thomson, J. R.; Phillips, J. A., III; Loyd, J. E.; Nichols,
W. C.; Trembath, R. C.: Heterozygous germline mutations in BMPR2,
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Genet. 26: 81-84, 2000.

15. Kingdon, H. S.; Cohen, L. S.; Roberts, W. C.; Braunwald, E.:
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Med. 118: 422-426, 1966.

16. Lee, S.-D.; Shroyer, K. R.; Markham, N. E.; Cool, C. D.; Voelkel,
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17. Li, X.; Zhang, X.; Leathers, R.; Makino, A.; Huang, C.; Parsa,
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J. H.: Heterogeneity of pathologic lesions in familial primary pulmonary
hypertension. Am. Rev. Resp. Dis. 138: 952-957, 1988.

20. Loyd, J. E.; Butler, M. G.; Foroud, T. M.; Conneally, P. M.; Phillips,
J. A., III; Newman, J. H.: Genetic anticipation and abnormal gender
ratio at birth in familial primary pulmonary hypertension. Am. J.
Resp. Crit. Care Med. 152: 93-97, 1995.

21. Loyd, J. E.; Primm, R. K.; Newman, J. H.: Familial primary pulmonary
hypertension: clinical patterns. Am. Rev. Resp. Dis. 129: 194-197,
1984.

22. Machado, R. D.; Eickelberg, O.; Elliott, C. G.; Geraci, M. W.;
Hanaoka, M.; Loyd, J. E.; Newman, J. H.; Phillips, J. A., III; Soubrier,
F.; Trembath, R. C.; Chung, W. K.: Genetics and genomics of pulmonary
arterial hypertension. J. Am. Coll. Cardiol. 54 (1 Suppl): S32-42,
2009.

23. Machado, R. D.; Rudarakanchana, N.; Atkinson, C.; Flanagan, J.
A.; Harrison, R.; Morrell, N. W.; Trembath, R. C.: Functional interaction
between BMPR-II and Tctex-1, a light chain of dynein, is isoform-specific
and disrupted by mutations underlying primary pulmonary hypertension. Hum.
Molec. Genet. 12: 3277-3286, 2003.

24. Melmon, K. L.; Braunwald, E.: Familial pulmonary hypertension. New
Eng. J. Med. 269: 770-775, 1963.

25. Morse, J. H.; Barst, R. J.; Fotino, M.: Familial pulmonary hypertension:
immunogenetic findings in four Caucasian kindreds. Am. Rev. Resp.
Dis. 145: 787-792, 1992.

26. Morse, J. H.; Barst, R. J.; Fotino, M.: Familial pulmonary hypertension:
immunogenetic findings in four Caucasian kindreds. Am. Rev. Resp.
Dis. 145: 787-792, 1992.

27. Morse, J. H.; Jones, A. C.; Barst, R. J.; Hodge, S. E.; Wilhelmsen,
K. C.; Nygaard, T. G.: Mapping of familial primary pulmonary hypertension
locus (PPH1) to chromosome 2q31-q32. Circulation 95: 2603-2606,
1997.

28. Newman, J. H.: Personal Communication. Nashville, Tenn. 7/21/1981.

29. Nichols, W. C.; Koller, D. L.; Slovis, B.; Foroud, T.; Terry,
V. H.; Arnold, N. D.; Siemieniak, D. R.; Wheeler, L.; Phillips, J.
A., III; Newman, J. H.; Conneally, P. M.; Ginsburg, D.; Loyd, J. E.
: Localization of the gene for familial primary pulmonary hypertension
to chromosome 2q31-32. Nature Genet. 15: 277-280, 1997.

30. Parry, W. R.; Verel, D.: Familial primary pulmonary hypertension. Brit.
Heart J. 28: 193-198, 1966.

31. Phillips, J. A., III; Poling, J. S.; Phillips, C. A.; Stanton,
K. C.; Austin, E. D.; Cogan, J. D.; Wheeler, L.; Yu, C.; Newman, J.
H.; Dietz, H. C.; Loyd, J. E.: Synergistic heterozygosity for TGF-beta-1
SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance
of familial pulmonary arterial hypertension. Genet. Med. 10: 359-365,
2008.

32. Rich, S.; Dantzker, D. R.; Ayres, S. M.; Bergofsky, E. H.; Brundage,
B. H.; Detre, K. M.; Fishman, A. P.; Goldring, R. M.; Groves, B. M.;
Koerner, S. K.; Levy, P. C.; Reid, L. M.; Vreim, C. E.; Williams,
G. W.: Primary pulmonary hypertension: a national prospective study. Ann.
Intern. Med. 107: 216-223, 1987.

33. Rigelsky, C. M.; Jennings, C.; Lehtonen, R.; Minai, O. A.; Eng,
C.; Aldred, M. A.: BMPR2 mutation in a patient with pulmonary arterial
hypertension and suspected hereditary hemorrhagic telangiectasia. Am.
J. Med. Genet. 146A: 2551-2556, 2008.

34. Rogge, J. D.; Mishkin, M. E.; Genovese, P. D.: The familial occurrence
of primary pulmonary hypertension. Ann. Intern. Med. 65: 672-684,
1966.

35. Rubin, L. J.: Primary pulmonary hypertension. New Eng. J. Med. 336:
111-117, 1997.

36. Said, S. I.; Hamidi, S. A.; Dickman, K. G.; Szema, A. M.; Lyubsky,
S.; Lin, R. Z.; Jiang, Y.-P.; Chen, J. J.; Waschek, J. A.; Kort, S.
: Moderate pulmonary arterial hypertension in male mice lacking the
vasoactive intestinal peptide gene. Circulation 115: 1260-1268,
2007.

37. Sankelo, M.; Flanagan, J. A.; Machado, R.; Harrison, R.; Rudarakanchana,
N.; Morrell, N.; Dixon, M.; Halme, M.; Puolijoki, H.; Kere, J.; Elomaa,
O.; Kupari, M.; Raisanen-Sokolowski, A.; Trembath, R. C.; Laitinen,
T.: BMPR2 mutations have short lifetime expectancy in primary pulmonary
hypertension. Hum. Mutat. 26: 119-124, 2005.

38. Shintani, M.; Yagi, H.; Nakayama, T.; Saji, T.; Matsuoka, R.:
A new nonsense mutation of SMAD8 associated with pulmonary arterial
hypertension. J. Med. Genet. 46: 331-337, 2009.

39. Thompson, P.; McRae, C.: Familial pulmonary hypertension. Evidence
of autosomal dominant inheritance. Brit. Heart J. 32: 758-760, 1970.

40. Thomson, J. R.; Machado, R. D.; Pauciulo, M. W.; Morgan, N. V.;
Humbert, M.; Elliott, G. C.; Ward, K.; Yacoub, M.; Mikhail, G.; Rogers,
P.; Newman, J.; Wheeler, L.; and 13 others: Sporadic primary pulmonary
hypertension is associated with germline mutations of the gene encoding
BMPR-II, a receptor member of the TGF-beta family. J. Med. Genet. 37:
741-745, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Decreased cardiac output;
Right ventricular hypertrophy;
Right ventricular failure;
Elevated right atrial pressure;
[Vascular];
Increased pulmonary artery pressure (mean greater than 25 mm Hg at
rest and 30 mm Hg during exercise);
Increased pulmonary vascular resistance;
Pulmonary artery vasoconstriction;
Arterial vascular wall remodeling;
Arteries show medial hypertrophy;
Arteries show intimal fibrosis;
Plexiform vascular lesions;
Thrombosis in situ

RESPIRATORY:
[Lung];
Dyspnea;
Pulmonary function tests may show restrictive pattern

HEMATOLOGY:
Thrombosis

LABORATORY ABNORMALITIES:
Arterial hypoxemia

MISCELLANEOUS:
Usually presents in third to fourth decade (but onset can range from
childhood to elderly);
Female to male ratio ranges from 2:1 to 4:1;
Prevalence in the Finnish population of 5.8 per million;
Incidence in the Finnish population of 0.2-1.3 cases per million per
year;
Incomplete penetrance

MOLECULAR BASIS:
Caused by mutation in the type 2 bone morphogenetic protein receptor
gene (BMPR2, 600799.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/15/2009
Cassandra L. Kniffin - updated: 8/14/2006
Cassandra L. Kniffin - revised: 4/12/2004

*FIELD* ED
ckniffin: 07/30/2013
ckniffin: 4/15/2009
ckniffin: 8/14/2006
joanna: 4/30/2004
ckniffin: 4/19/2004
ckniffin: 4/12/2004
alopez: 11/1/2002

*FIELD* CN
Ada Hamosh - updated: 02/11/2014
Cassandra L. Kniffin - updated: 7/30/2013
Marla J. F. O'Neill - updated: 6/10/2010
Ada Hamosh - updated: 2/18/2010
Marla J. F. O'Neill - updated: 12/2/2009
Marla J. F. O'Neill - updated: 7/15/2009
Cassandra L. Kniffin - updated: 6/15/2009
Cassandra L. Kniffin - updated: 4/15/2009
Marla J. F. O'Neill - updated: 4/5/2007
Cassandra L. Kniffin - updated: 8/14/2006
George E. Tiller - updated: 1/10/2006
Marla J. F. O'Neill - updated: 11/19/2004
Natalie E. Krasikov - updated: 3/30/2004
Victor A. McKusick - updated: 1/15/2004
John A. Phillips, III - updated: 11/1/2002
Victor A. McKusick - updated: 9/20/2001
John A. Phillips, III - updated: 8/11/2000
John A. Phillips, III - reorganized: 8/8/2000
Victor A. McKusick - updated: 3/30/1998
Paul Brennan - updated: 11/14/1997
Victor A. McKusick - updated: 3/2/1997
Victor A. McKusick - updated: 2/3/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 02/11/2014
carol: 7/31/2013
ckniffin: 7/30/2013
terry: 3/14/2013
carol: 1/9/2013
wwang: 7/1/2010
terry: 6/23/2010
wwang: 6/11/2010
terry: 6/10/2010
alopez: 2/25/2010
terry: 2/18/2010
carol: 12/9/2009
wwang: 12/7/2009
terry: 12/2/2009
wwang: 7/28/2009
terry: 7/15/2009
wwang: 6/29/2009
ckniffin: 6/15/2009
carol: 5/21/2009
wwang: 5/7/2009
ckniffin: 4/15/2009
wwang: 4/5/2007
wwang: 8/22/2006
ckniffin: 8/14/2006
wwang: 1/30/2006
terry: 1/10/2006
tkritzer: 11/19/2004
ckniffin: 4/30/2004
carol: 4/29/2004
ckniffin: 4/12/2004
terry: 3/30/2004
tkritzer: 1/21/2004
terry: 1/15/2004
alopez: 11/1/2002
mcapotos: 9/21/2001
terry: 9/20/2001
carol: 9/10/2001
terry: 1/19/2001
terry: 9/18/2000
alopez: 8/17/2000
alopez: 8/11/2000
joanna: 8/8/2000
dkim: 12/10/1998
carol: 4/13/1998
terry: 3/30/1998
alopez: 11/26/1997
alopez: 11/17/1997
alopez: 11/14/1997
mark: 3/3/1997
mark: 3/2/1997
terry: 2/28/1997
jamie: 2/18/1997
mark: 2/3/1997
terry: 1/22/1997
mimadm: 2/25/1995
carol: 9/25/1992
supermim: 3/16/1992
carol: 3/21/1991
carol: 10/11/1990
supermim: 3/20/1990

MIM 265450
*RECORD*
*FIELD* NO
265450
*FIELD* TI
#265450 PULMONARY VENOOCCLUSIVE DISEASE 1, AUTOSOMAL DOMINANT; PVOD1
;;PVOD
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
pulmonary venoocclusive disease-1 (PVOD1) is caused by heterozygous
mutation in the BMPR2 gene (600799) on chromosome 2q33.

DESCRIPTION

Pulmonary venoocclusive disease primarily affects the postcapillary
venous pulmonary vessels and may involve significant pulmonary capillary
dilation and/or proliferation. PVOD is an uncommon cause of pulmonary
artery hypertension (PPH; see 178600), a severe condition characterized
by elevated pulmonary artery pressure leading to right heart failure and
death. PVOD accounts for 5 to 10% of 'idiopathic' PPH and has an
estimated incidence of 0.1 to 0.2 cases per million. The pathologic
hallmark of PVOD is the extensive and diffuse occlusion of pulmonary
veins by fibrous tissue, with intimal thickening present in venules and
small veins in lobular septa and, rarely, larger veins. Definitive
diagnosis of PVOD requires histologic analysis of a lung sample,
although surgical lung biopsy is often too invasive for these frail
patients. Patients with PVOD respond poorly to available therapy,
therefore it is crucial to distinguish PVOD from other forms of PPH.
Radiologic characteristics suggestive of PVOD on high-resolution CT of
the chest include nodular ground-glass opacities, septal lines, and
lymph node enlargement. In addition, because PVOD mainly affects
postcapillary vasculature, it causes chronic elevation of pulmonary
capillary pressure and thus promotes occult alveolar hemorrhage, which
may be a characteristic feature of PVOD (summary by Montani et al.,
2008).

- Genetic Heterogeneity of Pulmonary Venoocclusive Disease

See also PVOD2 (234810), caused by mutation in the EIF2AK4 gene (609280)
on chromosome 15q15.

CLINICAL FEATURES

Voordes et al. (1977) reported pulmonary venoocclusive disease in a male
infant who died at the age of 3 months. Both intra- and extrapulmonary
veins were involved. A brother had died at the age of 8 weeks of the
same disease, limited to the intrapulmonary veins. They suggested that
this may have occurred in 2 sibs reported by Rosenthal et al. (1973).
They further suggested that the disease may be viral (not genetic), with
the mother serving as carrier, and that some instances of isolated
extraparenchymal pulmonary vein atresia or obstruction may be this
disorder.

Runo et al. (2003) studied a family in which the proband had PVOD and
her mother had severe primary pulmonary hypertension (see PPH1; 178600).
The proband presented at 36 years of age with dyspnea, prominent
pulmonary arteries on chest x-ray, and an elevated mean pulmonary artery
pressure of 53 mm Hg. Her disease was initially thought to be PPH, but
open lung biopsy revealed findings consistent with PVOD. The patient's
mother had died of complications of right heart failure; she had a mean
pulmonary artery pressure of 92 mm Hg on right heart catheterization,
absence of thromboembolic disease by pulmonary angiography, and no
evidence of secondary etiologies. Because lung biopsy and autopsy were
not performed, it was unknown whether the mother's pulmonary
hypertension was from PPH or PVOD.

Montani et al. (2008) retrospectively reviewed 48 cases of pulmonary
artery hypertension, including 24 patients with biopsy-proven PVOD and
24 patients with no evidence of PVOD after meticulous evaluation of lung
pathology. Compared to PPH, PVOD was characterized by a higher
male-to-female ratio and higher tobacco exposure. Clinical presentation
was similar except for a lower body mass index in PVOD patients. In
addition, at baseline PVOD patients had significantly lower partial
pressure of arterial oxygen, diffusing lung capacity of carbon monoxide
per alveolar volume, and oxygen saturation nadir during a 6-minute walk
test. Hemodynamic parameters showed a lower mean systemic arterial
pressure and right atrial pressure, but no difference in pulmonary
capillary wedge pressure. CT of the chest revealed nodular and
ground-glass opacities, septal lines, and lymph node enlargement more
frequently in patients with PVOD compared to patients with PPH (p less
than 0.05 for all). Seven (44%) of 16 PVOD patients who received
PPH-specific therapy developed pulmonary edema, and clinical outcomes
were worse for PVOD than PPH patients.

MOLECULAR GENETICS

In a family in which the proband had PVOD and her mother had pulmonary
hypertension, Runo et al. (2003) analyzed the BMPR2 gene and identified
heterozygosity for a 1-bp deletion (600799.0021) in the proband and her
unaffected sister. DNA was not available from their mother, who died of
right heart failure, or from the maternal grandparents.

In a patient with pulmonary arterial hypertension and PVOD, Machado et
al. (2006) identified heterozygosity for a nonsense mutation
(600799.0022) in the BMPR2 gene.

In a patient with primary pulmonary hypertension and histologic features
of PVOD, Aldred et al. (2006) identified heterozygosity for a deletion
of exon 2 of the BMPR2 gene (600799.0023). The patient had 3 affected
relatives, all of whom were deceased. The same deletion was identified
in an unrelated family with primary pulmonary hypertension and no known
evidence of PVOD.

In a cohort of 48 patients with PPH, 24 of whom had histologic evidence
of PVOD, Montani et al. (2008) identified mutations in the BMPR2 gene in
2 patients with PVOD (600799.0027 and 600799.0028) and in 4 patients
with no evidence of PVOD.

*FIELD* RF
1. Aldred, M. A.; Vijayakrishnan, J.; James, V.; Soubrier, F.; Gomez-Sanchez,
M. A.; Martensson, G.; Galie, N.; Manes, A.; Corris, P.; Simonneau,
G.; Humbert, M.; Morrell, N. W.; Trembath, R. C.: BMPR2 gene rearrangements
account for a significant proportion of mutations in familial and
idiopathic pulmonary arterial hypertension. (Abstract) Hum. Mutat. 27:
212-213, 2006. Note: Full article online.

2. Machado, R. D.; Aldred, M. A.; James, V.; Harrison, R. E.; Patel,
B.; Schwalbe, E. C.; Gruenig, E.; Janssen, B.; Koehler, R.; Seeger,
W.; Eickelberg, O.; Olschewski, H.; and 21 others: Mutations of
the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum.
Mutat. 27: 121-132, 2006.

3. Montani, D.; Achouh, L.; Dorfmuller, P.; Le Pavec, J.; Sztrymf,
B.; Tcherakian, C.; Rabiller, A.; Haque, R.; Sitbon, O.; Jais, X.;
Dartevelle, P.; Maitre, S.; Capron, F.; Musset, D.; Simonneau, G.;
Humbert, M.: Pulmonary veno-occlusive disease: clinical, functional,
radiologic, and hemodynamic characteristics and outcome of 24 cases
confirmed by histology. Medicine 87: 220-233, 2008.

4. Rosenthal, A.; Vawter, G. F.; Wagenvoorst, C. A.: Intrapulmonary
veno-occlusive disease. Am. J. Cardiol. 31: 78-83, 1973.

5. Runo, J. R.; Vnencak-Jones, C. L.; Prince, M.; Loyd, J. E.; Wheeler,
L.; Robbins, I. M.; Lane, K. B.; Newman, J. H.; Johnson, J.; Nichols,
W. C.; Phillips, J. A., III.: Pulmonary veno-occlusive disease caused
by an inherited mutation in bone morphogenetic protein receptor II. Am.
J. Resp. Crit. Care Med. 167: 889-894, 2003.

6. Voordes, C. G.; Kuipers, J. R. G.; Elema, J. D.: Familial pulmonary
veno-occlusive disease: a case report. Thorax 32: 763-766, 1977.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Prominent second heart sound;
[Vascular];
Elevated jugular venous pressure;
Pulmonary arterial hypertension

RESPIRATORY:
[Lung];
Pulmonary veno-occlusive disease seen on biopsy;
Centrilobular ground glass opacities seen on CT;
Thickened interlobular septae seen on CT;
Occult alveolar hemorrhage

MISCELLANEOUS:
Variable clinical presentation

MOLECULAR BASIS:
Caused by mutation in the bone morphogenetic receptor, type II gene
(BMPR2, 600799.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 06/04/2013
Joanna S. Amberger - revised: 1/10/2013

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

*FIELD* ED
joanna: 06/04/2013
joanna: 1/10/2013

*FIELD* CN
Marla J. F. O'Neill - updated: 1/16/2013
Marla J. F. O'Neill - updated: 4/5/2007

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

*FIELD* ED
carol: 02/12/2014
ckniffin: 2/5/2014
carol: 1/23/2013
terry: 1/16/2013
carol: 1/9/2013
wwang: 4/20/2009
wwang: 4/5/2007
mimadm: 3/12/1994
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/25/1986

MIM 600799
*RECORD*
*FIELD* NO
600799
*FIELD* TI
*600799 BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II; BMPR2
*FIELD* TX

DESCRIPTION
read more
Bone morphogenetic proteins (BMPs) are a family of proteins that induce
bone formation at extracellular sites in vivo. BMPs act on osteoblasts
and chondrocytes as well as other cell types, including neurocells, and
they play important roles in embryonal development. Members of the BMP
family include BMP1 (112264) to BMP6 (112266), BMP7 (112267), also
called osteogenic protein-1 (OP1), OP2 (BMP8; 602284), and others. BMPs
belong to the transforming growth factor beta (TGF-beta) superfamily,
which includes, in addition to the TGF-betas (e.g., 190180),
activin/inhibins (e.g., alpha-inhibin; 147380), mullerian inhibiting
substance (600957), and glial cell line-derived neurotrophic factor
(600837). TGF-betas and activins transduce their signals through the
formation of heteromeric complexes of 2 different types of serine
(threonine) kinase receptors: type I receptors of about 50 to 55 kD and
type II receptors of about 70 to 80 kD. Type II receptors bind ligands
in the absence of type I receptors, but they require their respective
type I receptors for signaling, whereas type I receptors require their
respective type II receptors for ligand binding. BMPR2 is a type II
receptor for BMPs.

CLONING

Rosenzweig et al. (1995) reported the cDNA cloning and characterization
of a human type II receptor for BMPs, which they called BMPR II, that is
distantly related to DAF4, a BMP type II receptor in Caenorhabditis
elegans.

MAPPING

By analysis of a monochromosome hybrid mapping panel and by FISH, Astrom
et al. (1999) mapped the BMPR2 gene to chromosome 2q33-q34.

GENE FUNCTION

Rosenzweig et al. (1995) showed that, in transfected COS-1 cells, BMP7
and, less efficiently, BMP4 (112262) bound to BMPR II. BMPR II bound
ligands only weakly alone, but the binding was facilitated by the
presence of previously identified type I receptors for BMPs. A
transcriptional activation signal was transduced by BMPR II in the
presence of type I receptors after stimulation by BMP7.

In an investigation of the molecular bases of common nonfamilial forms
of pulmonary hypertension, Du et al. (2003) evaluated the pattern of
expression of several genes in lung biopsy specimens from patients with
pulmonary hypertension and from normotensive control patients. The genes
included angiopoietin-1 (ANGPT1; 601667), a protein involved in the
recruitment of smooth muscle cells around blood vessels; TIE2 (600221),
the endothelial-specific receptor for angiopoietin-1; bone morphogenetic
protein receptor 1A (BMPR1A; 601299); and BMPR2. The effect of
angiopoietin-1 on the modulation of BMPR expression was also evaluated
in subcultures of human pulmonary arteriolar endothelial cells. The
expression of angiopoietin-1 mRNA and the protein itself and the
phosphorylation of TIE2 were strongly upregulated in the lungs of
patients with various forms of pulmonary hypertension, correlating
directly with the severity of disease. A mechanistic link between
familial and acquired pulmonary hypertension was demonstrated by the
finding that angiopoietin-1 shuts off the expression of BMPR1A, a
transmembrane protein required for BMPR2 signaling, in pulmonary
arteriolar endothelial cells. Similarly, the expression of BMPR1A was
severely reduced in the lungs of patients with various forms of acquired
as well as primary nonfamilial pulmonary hypertension. The findings
suggested that all forms of pulmonary hypertension are linked by defects
in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and
BMPR2, and consequently identified specific molecular targets for
therapeutic intervention.

Machado et al. (2003) determined that TCTEL1 (601554), a light chain of
the motor complex dynein, interacted with the cytoplasmic domain of
BMPR2 and was also phosphorylated by BMPR2, a function disrupted by
primary pulmonary hypertension (PPH1; 178600)-causing mutations within
exon 12 (e.g., 600799.0002). BMPR2 and TCTEL1 colocalized to endothelium
and smooth muscle within the media of pulmonary arterioles, key sites of
vascular remodeling in PPH. The authors proposed that loss of
interaction and lack of phosphorylation of TCTEL1 by BMPR2 may
contribute to the pathogenesis of PPH.

Using RT-PCR, immunofluorescence, and flow cytometric analyses, Cejalvo
et al. (2007) demonstrated that human thymus and cortical epithelial
cells produced BMP2 (112261) and BMP4 and that both thymocytes and
thymic epithelium expressed the molecular machinery to respond to these
proteins. The receptors BMPR1A and BMPR2 were mainly expressed by
cortical thymocytes, whereas BMPR1B (603248) was expressed in the
majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal
thymic organ cultures seeded with CD34 (142230)-positive human thymic
progenitors resulted in reduced cell recovery and inhibition of
differentiation of CD4 (186940)/CD8 (see 186910) double-negative to
double-positive stages. Cejalvo et al. (2007) concluded that BMP2 and
BMP4 have a role in human T-cell differentiation.

Tsang et al. (2009) showed that mammalian NIPA1 (608145) is an inhibitor
of BMP signaling. NIPA1 physically interacted with the BMPR2, and this
interaction did not require the cytoplasmic tail of BMPR2. The mechanism
by which NIPA1 inhibited BMP signaling involved downregulation of BMP
receptors by promoting their endocytosis and lysosomal degradation.
Disease-associated mutant versions of NIPA1 altered the trafficking of
BMPR2 and were less efficient at promoting BMPR2 degradation than
wildtype NIPA1. In addition, 2 other members of the endosomal group of
hereditary spastic paraplegia (HSP) proteins, spastin (SPAST; 604277)
and spartin (SPG20; 607111), inhibited BMP signaling. Since BMP
signaling is important for distal axonal function, Tsang et al. (2009)
proposed that dysregulation of BMP signaling could be a unifying
pathologic component in this endosomal group of HSPs, and perhaps of
importance in other conditions in which distal axonal degeneration is
found.

Davis et al. (2008) demonstrated that induction of a contractile
phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is
mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in
turn acts as a negative regulator of smooth muscle contractile genes.
Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in
expression of mature miR21 through a posttranscriptional step, promoting
the processing of primary transcripts of miR21 (pri-miR21) into
precursor miR21 (pre-miR21) by the Drosha complex (608828). TGF-beta and
BMP-specific SMAD signal transducers SMAD1 (601595), SMAD2 (601366),
SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a
complex with the RNA helicase p68 (DDX5; 180630), a component of the
Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not
required for this process. Davis et al. (2008) concluded that regulation
of microRNA biogenesis by ligand-specific SMAD proteins is critical for
control of the vascular smooth muscle cell phenotype and potentially for
SMAD4-independent responses mediated by the TGF-beta and BMP signaling
pathways.

In a follow-up to the report of Davis et al. (2008), Drake et al. (2011)
found that BMPR2 was essential for the SMAD-mediated miR processing.
Loss of SMAD9 (603295) also affected miR processing in smooth muscle
cells and in endothelial cells, but it did not affect canonical BMP
signaling. Knockdown of individual receptor SMADs 1, 5, and 9 decreased
levels of processed miR21 levels in both types of cells, suggesting that
the miR processing pathway forms a complex.

MOLECULAR GENETICS

The International PPH Consortium et al. (2000) and Deng et al. (2000)
reported that mutations in the BMPR2 gene can cause primary pulmonary
hypertension (PPH), a locus for which resides on chromosome 2q33 (PPH1;
178600). BMPR2 mutations were found in 7 of 8 of the PPH1 families
exhibiting linkage to markers adjacent to BMPR2 by the International PPH
Consortium et al. (2000) and in 9 of 19 of the families exhibiting
linkage and/or haplotype sharing with markers adjacent to BMPR2 by Deng
et al. (2000). Both groups reported heterogeneous BMPR2 mutations that
included termination, frameshift, and nonconservative missense changes
in amino acid sequence.

Thomson et al. (2000) analyzed the BMPR2 gene in 50 unrelated patients
with apparent sporadic PPH and identified 11 different heterozygous
mutations in 13 of the 50 PPH patients, including 3 missense, 3 nonsense
(see, e.g., 600799.0019), and 5 frameshift mutations. Analysis of
parental DNA was possible in 5 cases and showed 3 occurrences of
paternal transmission and 2 of de novo mutation of the BMPR2 gene.
Thomson et al. (2000) noted that because of low penetrance, in the
absence of detailed genealogic data, familial cases may be overlooked.

Machado et al. (2001) reported the molecular spectrum of BMPR2 mutations
in 47 families with PPH and in 3 patients with sporadic PPH. In the
cohort of patients, they identified 22 novel mutations, including 4
partial deletions, distributed throughout the BMPR2 gene. The majority
(58%) of mutations were predicted to lead to a premature termination
codon. In vitro expression analysis demonstrated loss of BMPR2 function
for a number of the identified mutations. These data suggested that
haploinsufficiency represents the common molecular mechanism in PPH.
Marked variability of the age at onset of disease was observed both
within and between families. The observed overall range for the age at
onset of symptoms of PPH was 1 to 60 years. In 1 family, the age at
onset for the 8 affected individuals ranged from 14 to 60 years. The
authors interpreted these observations as indicating that additional
factors, genetic and/or environmental, may be required for the
development of the clinical phenotype.

Most patients with primary pulmonary hypertension are thought to have
sporadic, not inherited, disease. Because clinical disease develops in
only 10 to 20% of persons carrying the gene for familial primary
pulmonary hypertension, Newman et al. (2001) hypothesized that many
patients with apparently sporadic primary pulmonary hypertension may
actually have familial primary pulmonary hypertension. Over a period of
20 years, they developed a registry of 67 families affected by familial
primary pulmonary hypertension. They discovered shared ancestry among 5
subfamilies, including 394 known members spanning several generations,
which were traced back to a founding couple in the mid-1800s. PPH had
been diagnosed in 18 family members, 12 of whom were first thought to
have sporadic disease. In 7 of the 18, the initial misdiagnosis was
another form of cardiopulmonary disease. The cys118-to-trp mutation
(600799.0005) was found in 6 members affected by PPH and in 6
individuals who were from the pedigree recognized as being carriers.

To determine the mechanism of altered BMPR2 function in primary
pulmonary hypertension, Rudarakanchana et al. (2002) transiently
transfected pulmonary vascular smooth muscle cells with mutant BMPR2
constructs and fusion proteins. Substitution of cysteine residues in the
ligand binding (i.e., 600799.0005, 600799.0016) or kinase (600799.0006)
domain prevented trafficking of BMPR2 to the cell surface, and reduced
binding of radiolabeled BMP4. In addition, transfection of
cysteine-substituted BMPR2 markedly reduced basal and BMP4-stimulated
transcriptional activity of a BMP/SMAD-responsive luciferase reporter
gene (3GC2wt-Lux), compared with wildtype BMPR2, suggesting a
dominant-negative effect of these mutants on SMAD signaling. In
contrast, BMPR2 containing noncysteine substitutions in the kinase
domain (600799.0007, 600799.0008, 600799.0013) were localized to the
cell membrane, although these also suppressed the activity of
3GC2wt-Lux. Interestingly, BMPR2 mutations within the cytoplasmic tail
(600799.0002) trafficked to the cell surface, but retained the ability
to activate 3GC2wt-Lux. Transfection of mutant, but not wildtype,
constructs into a mouse epithelial cell line led to activation of p38
MAPK (MAPK14; 600289) and increased serum-induced proliferation compared
with the wildtype receptor, which was partly p38 MAPK-dependent. The
authors concluded that mutations in BMPR2 heterogeneously inhibit
BMP/SMAD-mediated signaling by diverse molecular mechanisms. However,
all mutants studied demonstrate a gain of function involving
upregulation of p38 MAPK-dependent pro-proliferative pathways.

Humbert et al. (2002) analyzed the BMPR2 gene in 33 unrelated patients
with sporadic PPH and 2 sisters with PPH, all of whom had taken
fenfluramine derivatives. Three BMPR2 mutations (see, e.g., 600799.0020)
were identified in 3 (9%) of the 33 unrelated patients, and a fourth
mutation (R211X; 600799.0019) was identified in the 2 sisters. The
latter mutation, as well as 1 of the sporadic mutations, had previously
been identified in patients with PPH unassociated with fenfluramine
derivatives.

In a family in which the proband had pulmonary venoocclusive disease
(PVOD1; 265450) and her mother had pulmonary hypertension, Runo et al.
(2003) analyzed the BMPR2 gene and identified heterozygosity for a 1-bp
deletion (600799.0021) in the proband and her unaffected sister. DNA was
not available from their mother, who had known pulmonary hypertension
and died of right heart failure, or from the maternal grandparents.

In a patient with pulmonary arterial hypertension and PVOD, Machado et
al. (2006) identified heterozygosity for a nonsense mutation
(600799.0022) the BMPR2 gene.

In 25 families with PPH and 106 patients with sporadic PPH, all of whom
were negative for mutations in the BMPR2 gene by DHPLC analysis or
direct sequencing, Aldred et al. (2006) performed multiplex
ligation-dependent probe amplification (MLPA) analysis to detect gross
BMPR2 rearrangements. Ten different deletions were identified in 7
families and 6 sporadic cases (see, e.g., 600799.0023-600799.0025). One
patient with familial PPH had histologic features of pulmonary
venoocclusive disease and was found to have a deletion of exon 2 of the
BMPR2 gene (600799.0023); the exon 2 deletion was also identified in an
unrelated family with PPH and no known evidence of PVOD. Aldred et al.
(2006) noted that 2 large deletions were predicted to result in null
alleles (see 600799.0025), providing support for the hypothesis that the
predominant molecular mechanism for disease predisposition is
haploinsufficiency.

Phillips et al. (2008) studied SNP genotypes of TGF-beta (190180) in
BMPR2 mutation carriers with pulmonary hypertension and examined the age
of diagnosis and penetrance of the pulmonary hypertension phenotype.
BMPR2 heterozygotes with least active -509 or codon 10 TGFB1 SNPs had
later mean age at diagnosis of familial pulmonary arterial hypertension
(39.5 and 43.2 years, respectively), than those with more active
genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively).
Kaplan-Meier analysis showed that those with less active SNPs had later
age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated
decay (NMD)-resistant BMPR2 mutations and the least, intermediate, and
most active -509 TGFB1 SNP phenotypes had penetrances of 33%, 72%, and
80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active
SNP alleles had penetrances of 33%, 72%, and 75% (P = 0.005). Phillips
et al. (2008) concluded that the TGFB1 SNPs studied modulate age at
diagnosis and penetrance of familial pulmonary arterial hypertension in
BMPR2 mutation heterozygotes, likely by affecting TGFB/BMP signaling
imbalance. The authors considered this modulation an example of
synergistic heterozygosity.

Using enzymatic and fluorescence activity-based techniques, Nasim et al.
(2008) demonstrated that PPH-causing nonsense and frameshift BMPR2
mutations (see, e.g., 600799.0002) trigger NMD, providing further
evidence that haploinsufficiency is a major molecular consequence of
disease-related BMPR2 mutations. Missense mutations (see, e.g.,
600799.0006, 600799.0007, and 600799.0013) resulted in heterogeneous
functional defects in BMPR2 activity, including impaired phosphorylation
of the type 1 receptors BMPR1A and BMPR1B (603248), reduced
receptor-receptor interactions, and altered receptor complex
stoichiometry leading to perturbation of downstream signaling pathways.
Nasim et al. (2008) concluded that the intracellular domain of BMPR2 is
both necessary and sufficient for receptor complex interaction, and
suggested that stoichiometric imbalance, due to either
haploinsufficiency or loss of optimal receptor-receptor interactions,
impairs BMPR2-mediated signaling in PPH.

In a cohort of 48 patients with PAH, 24 of whom had histologic evidence
of PVOD, Montani et al. (2008) identified mutations in the BMPR2 gene in
2 patients with PVOD (600799.0027 and 600799.0028) and in 4 patients
with no evidence of PVOD.

In pulmonary endothelial cells derived from 2 of 3 PPH1 patients with
BMPR2 mutations, Drake et al. (2011) found loss of miR21 induction in
response to BMP9. These cells also showed greater proliferation compared
to controls; overexpression of miR21 induced growth suppression.
However, canonical BMP signaling was only mildly attenuated in these
cells. The findings suggested that disruption of the noncanonical
BMP-mediated pathway resulting in aberrant miR processing may play an
important role in the pathogenesis of PPH.

*FIELD* AV
.0001
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, 1-BP DEL, 2579T

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported deletion of a T in
an ATT repeat (2579delT) in exon 12 of the BMPR2 gene. This frameshift
mutation was predicted to result in premature termination after 10 amino
acid residues. The resulting truncation includes the large cytoplasmic
domain of the 1,038-amino acid BMPR2 protein. The authors concluded that
this mutation is likely to impede heteromeric receptor complex formation
at the cell surface, a requirement for normal signal transduction. They
also concluded that the mechanism of PPH1 causation may be either
haploinsufficiency or a dominant-negative mechanism. In a family with
primary pulmonary hypertension, Deng et al. (2000) independently
identified the 2579delT mutation.

.0002
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG899TER

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported a nonsense mutation
in exon 12 of the BMPR2 gene, an arg899-to-ter (R899X) substitution that
was caused by a C-to-T transition at base 2695. This termination
mutation was predicted to truncate the large cytoplasmic domain of the
1,038-amino acid BMPR2 protein. The authors concluded that this mutation
is likely to impede heteromeric receptor complex formation at the cell
surface.

.0003
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, SER73TER

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported a nonsense mutation
in exon 2 of the BMPR2 gene, ser73-to ter (S73X), that was caused by a
C-to-G transversion at base 218. This termination mutation was predicted
to truncate the protein before the transmembrane domain; if translated,
the protein may fail to reach the cell surface.

.0004
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, 1-BP DEL, 355A

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported a deletion of an A
in exon 3 of the BMPR2 gene at position 355. This frameshift mutation
was predicted to result in a premature termination that would truncate
the protein before the transmembrane domain; if translated, the protein
may fail to reach the cell surface.

.0005
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, CYS118TRP

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported a T-to-G
transversion at position 354 of the BMPR2 gene resulting in a
cys118-to-trp (C118W) substitution. This amino acid substitution, which
occurs at a highly conserved and functionally important site of the
BMPR2 protein, was predicted to perturb ligand binding.

.0006
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, CYS347TYR

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported a G-to-A transition
at position 1042 in exon 8 of the BMPR2 gene resulting in a
cys347-to-tyr (C347Y) substitution. This amino acid substitution occurs
at a highly conserved and functionally important site of the BMPR2
protein.

.0007
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ASP485GLY

In a family with primary pulmonary hypertension (PPH1; 178600), the
International PPH Consortium et al. (2000) reported an A-to-G transition
at position 1454 in exon 11 of the BMPR2 gene that was predicted to
result in an asp485-to-gly (D485G) substitution. This amino acid
substitution occurs at a highly conserved and functionally important
site of the BMPR2 protein.

.0008
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG491TRP

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a C-to-T transition at position 1471 in exon 11 of
the BMPR2 gene that was predicted to result in an arg491-to-trp (R491W)
substitution. This amino acid substitution occurs at an arginine that is
highly conserved in all type II TGF-beta receptors and appears to be
homologous to the invariant arg280 in subdomain XI in other protein
kinases (Hanks et al., 1988).

.0009
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, 5-BP DEL, NT1099

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a GGGGA deletion at position 1099-1103 in exon 8 of
the BMPR2 gene that results in a frameshift and premature termination of
the BMPR2 protein following codon 368.

.0010
MOVED TO 600799.0001
.0011
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, CYS169TER

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a 4-bp deletion (CTTT) and 3-bp insertion (AAA) at
position 507-510 in exon 4 of the BMPR2 gene that results in premature
termination of the BMPR2 protein, changing cysteine-169 to ter (C169X).

.0012
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG873TER

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a C-to-T transition at position 2617 in exon 12 of
the BMPR2 gene that was predicted to result in an arg873-to-ter mutation
(R873X).

.0013
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG491GLN

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a G-to-A transition at position 1472 in exon 11 of
the BMPR2 gene that was predicted to result in an arg491-to-gln mutation
(R491Q). This amino acid substitution occurs at an arginine that is
highly conserved in all type II TGF-beta receptors and appears to be
homologous to arg280 in subdomain XI in other protein kinases (Hanks et
al., 1988).

.0014
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, 2-BP DEL, 1-BP INS, NT690

In a family with primary pulmonary hypertension (PPH1; 178600), Deng et
al. (2000) reported a 2-bp deletion (AG) and 1-bp insertion (T) at
position 690-691 in exon 6 of the BMPR2 gene that results in a
frameshift leading to premature termination of the BMPR2 protein 21
amino acid residues following codon 230.

.0015
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, CYS123ARG

In 2 affected members of the same generation of a family with primary
pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified
a T-to-C transition at nucleotide 367 of the BMPR2 gene, predicted to
result in a cys123-to-arg substitution. The ages of onset were 9 and 26
years.

.0016
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, CYS123SER

In 5 affected members of 2 generations of a family with primary
pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified
a T-to-A transversion at nucleotide 367 of the BMPR2 gene, predicted to
result in a cys123-to-ser substitution.

.0017
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG332TER

In 2 apparently unrelated families, Machado et al. (2001) found that
multiple members affected by primary pulmonary hypertension (PPH1;
178600) carried a C-to-T transition at nucleotide 994 of the BMPR2 gene,
resulting in an arg332-to-ter mutation. In one family, a parent and
child were affected, with onset at 28 and 32 years of age; in the other
family, 8 members of 3 generations were affected with an age of onset
ranging from 13 to 42 years.

.0018
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, ARG899PRO

In a Finnish patient with primary pulmonary hypertension (PPH1; 178600),
Sankelo et al. (2005) identified a heterozygous 2696G-C transversion in
exon 12 of the BMPR2 gene, resulting in an arg899-to-pro (R899P)
substitution in the C-terminal cytoplasmic domain. Functional expression
studies showed that the R899P mutation resulted in constitutive
activation of MAPK14 (600289). A nonsense mutation at the same codon
(R899X; 600799.0002) had previously been reported.

.0019
PULMONARY HYPERTENSION, PRIMARY, 1
PULMONARY HYPERTENSION, PRIMARY, DEXFENFLURAMINE-ASSOCIATED, INCLUDED
BMPR2, ARG211TER

In a patient with sporadic primary pulmonary hypertension (PPH1;
178600), Thomson et al. (2000) identified heterozygosity for a 631C-T
transition in exon 6 of the BMPR2 gene, resulting in an arg211-to-ter
(R211X) substitution. The mutation was not found in 150 normal
chromosomes.

Machado et al. (2001) found the R211X mutation in 2 affected members of
the same generation of an Italian family with primary pulmonary
hypertension. Age of onset of disease was 17 and 18 years, respectively.

Humbert et al. (2002) analyzed the BMPR2 gene in 2 sisters who developed
pulmonary arterial hypertension after 1 and 2 months' exposure to
dexfenfluramine, respectively, and identified the R211X mutation in both
sisters. The mutation was not found in 260 ethnically matched control
chromosomes.

.0020
PULMONARY HYPERTENSION, PRIMARY, FENFLURAMINE-ASSOCIATED
BMPR2, GLY182ASP

In a patient who developed pulmonary arterial hypertension (PPH1;
178600) after taking fenfluramine for 2 months, Humbert et al. (2002)
identified a 545G-A transition in exon 5 of the BMPR2 gene, resulting in
a gly182-to-asp (G182D) substitution in the kinase domain of the
protein.

.0021
PULMONARY HYPERTENSION, PRIMARY, 1
PULMONARY VENOOCCLUSIVE DISEASE 1, INCLUDED
BMPR2, 1-BP DEL, 44C

In 2 affected members from 2 generations of a family with primary
pulmonary hypertension (PPH1; 178600), Machado et al. (2001) identified
heterozygosity for a 1-bp deletion in exon 1 of the BMPR2 gene (44delC),
predicted to cause premature termination of the protein 30 codons
downstream. Age at onset of disease was 36 and 38 years, respectively.

In a woman who presented with pulmonary venoocclusive disease (PVOD1;
265450) at age 36, Runo et al. (2003) identified heterozygosity for the
44delC mutation in the BMPR2 gene. The patient's deceased mother was
known to have had pulmonary hypertension and died of complications of
right heart failure; because lung biopsy and autopsy were not performed,
it was unknown whether the mother's pulmonary hypertension was from PPH
or PVOD.

.0022
PULMONARY VENOOCCLUSIVE DISEASE 1
BMPR2, TYR40TER

In a patient with pulmonary arterial hypertension and pulmonary
venoocclusive disease (265450), Machado et al. (2006) identified
heterozygosity for a 120T-G transversion in exon 2 of the BMPR2 gene,
resulting in a tyr40-to-ter (Y40X) substitution.

.0023
PULMONARY HYPERTENSION, PRIMARY, 1
PULMONARY VENOOCCLUSIVE DISEASE 1, INCLUDED
BMPR2, EX2DEL

In the probands of 2 families with primary pulmonary hypertension (PPH1;
178600), Aldred et al. (2006) identified heterozygosity for deletion of
exon 2 of the BMPR2 gene, predicted to result in loss of 57 amino acids
from the extracellular ligand-binding domain. The affected relatives, 1
in the first family and 3 in the second, were all deceased. The proband
of the second family had histologic features of pulmonary venoocclusive
disease (PVOD1; 265450).

.0024
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, EX10DEL

In 2 sibs and an unrelated pediatric patient with primary pulmonary
hypertension (PPH1; 178600), Aldred et al. (2006) identified
heterozygosity for deletion of exon 10 of the BMPR2 gene, resulting in
loss of 45 amino acids from the kinase domain. The deletion was
predicted to cause a frameshift and premature termination of exon 11
that was expected to result in nonsense-mediated decay (NMD). The sibs
inherited the mutation from their unaffected father; in the other case,
the mutation was inherited from the unaffected mother.

.0025
PULMONARY HYPERTENSION, PRIMARY, 1
BMPR2, EX1-13DEL

In a patient with primary pulmonary hypertension (PPH1; 178600), Aldred
et al. (2006) identified heterozygosity for a deletion of exons 1
through 13 in the BMPR2 gene, confirmed to extend into the 5-prime
untranslated region and predicted to result in a complete null allele.
The mutation was not found in either parent.

.0026
PULMONARY HYPERTENSION, PRIMARY, 1, WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA
BMPR2, GLN433TER

In a woman with primary pulmonary hypertension (PPH1; 178600) diagnosed
at age 24 years, Rigelsky et al. (2008) identified a heterozygous
1297C-T transition in exon 10 of the BMPR2 gene, resulting in a
gln433-to-ter (Q433X) substitution. She developed massive hemoptysis at
age 35, prompting the discovery of multiple pulmonary arteriovenous
malformations consistent with a diagnosis of hereditary hemorrhagic
telangiectasia (HHT). She also had recurrent epistaxis and nasal
telangiectasia. The patient was adopted, and there was no family history
available. Rigelsky et al. (2008) noted that, although PAH with HHT had
usually only been associated with mutations in the ACVRL1 gene (601284),
their patient was the first report of PAH and HHT associated with a
mutation in the BMPR2 gene. The findings indicated a common molecular
pathogenesis in PAH and HHT, most likely dysregulated BMP9 (GDF2;
605120) signaling.

.0027
PULMONARY VENOOCCLUSIVE DISEASE 1
BMPR2, ASN202TYR

Montani et al. (2008) reported a patient with pulmonary artery
hypertension who had histologic evidence of pulmonary venoocclusive
disease (PVOD1; 265450) and a heterozygous 604A-T transversion in exon 5
of the BMPR2 gene, resulting in an asn202-to-tyr (N202Y) substitution.

.0028
PULMONARY VENOOCCLUSIVE DISEASE 1
BMPR2, GLU195TER

Montani et al. (2008) reported a patient with pulmonary artery
hypertension who had histologic evidence of pulmonary venoocclusive
disease (PVOD1; 265450) and a heterozygous 583G-T transversion in exon 5
of the BMPR2 gene, resulting in a glu195-to-ter (E195X) substitution.

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H.; Dietz, H. C.; Loyd, J. E.: Synergistic heterozygosity for TGF-beta-1
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18. Rigelsky, C. M.; Jennings, C.; Lehtonen, R.; Minai, O. A.; Eng,
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19. Rosenzweig, B. L.; Imamura, T.; Okadome, T.; Cox, G. N.; Yamashita,
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21. Runo, J. R.; Vnencak-Jones, C. L.; Prince, M.; Loyd, J. E.; Wheeler,
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*FIELD* CN
Cassandra L. Kniffin - updated: 7/30/2013
Marla J. F. O'Neill - updated: 1/16/2013
Paul J. Converse - updated: 10/12/2010
Marla J. F. O'Neill - updated: 8/25/2010
George E. Tiller - updated: 8/6/2010
Ada Hamosh - updated: 2/18/2010
Cassandra L. Kniffin - updated: 4/15/2009
Marla J. F. O'Neill - updated: 4/5/2007
Cassandra L. Kniffin - updated: 8/14/2006
George E. Tiller - updated: 1/10/2006
Patricia A. Hartz - updated: 3/22/2004
George E. Tiller - updated: 5/29/2003
Victor A. McKusick - updated: 2/10/2003
Victor A. McKusick - updated: 9/20/2001
Victor A. McKusick - updated: 1/23/2001
John A. Phillips, III - updated: 8/11/2000

*FIELD* CD
Victor A. McKusick: 9/25/1995

*FIELD* ED
carol: 02/12/2014
carol: 9/16/2013
carol: 7/31/2013
ckniffin: 7/30/2013
carol: 1/23/2013
terry: 1/16/2013
terry: 9/25/2012
wwang: 3/2/2011
mgross: 10/18/2010
terry: 10/12/2010
wwang: 8/27/2010
terry: 8/25/2010
wwang: 8/9/2010
terry: 8/6/2010
alopez: 2/25/2010
terry: 2/18/2010
terry: 6/4/2009
wwang: 5/7/2009
ckniffin: 4/15/2009
wwang: 4/13/2007
wwang: 4/5/2007
wwang: 8/22/2006
ckniffin: 8/14/2006
wwang: 1/31/2006
wwang: 1/30/2006
terry: 1/10/2006
mgross: 3/31/2004
terry: 3/22/2004
cwells: 5/29/2003
carol: 2/25/2003
tkritzer: 2/21/2003
terry: 2/10/2003
carol: 11/19/2001
mcapotos: 10/2/2001
mcapotos: 9/27/2001
mcapotos: 9/20/2001
terry: 9/20/2001
carol: 1/24/2001
mgross: 1/24/2001
terry: 1/23/2001
terry: 1/19/2001
terry: 11/9/2000
terry: 9/18/2000
alopez: 8/11/2000
dkim: 11/6/1998
mark: 11/11/1996
mark: 12/12/1995
terry: 11/13/1995
mark: 9/25/1995