RBCC

Full text data of ENG

ENG (END) [Confidence: high (a blood group or CD marker)]
Endoglin (CD105; Flags: Precursor)

UniProt P17813
ID EGLN_HUMAN Reviewed; 658 AA.
AC P17813; Q14248; Q14926; Q5T9C0;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1998, sequence version 2.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Endoglin;
DE AltName: CD_antigen=CD105;
DE Flags: Precursor;
GN Name=ENG; Synonyms=END;
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] (ISOFORM SHORT).
RX PubMed=8370410; DOI=10.1002/eji.1830230943;
RA Bellon T., Corbi A., Lastres P., Cales C., Cebrian M., Vera S.,
RA Cheifetz S., Massague J., Letarte M., Bernabeu C.;
RT "Identification and expression of two forms of the human transforming
RT growth factor-beta-binding protein endoglin with distinct cytoplasmic
RT regions.";
RL Eur. J. Immunol. 23:2340-2345(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 14-658, AND PROTEIN
RP SEQUENCE OF 26-36 (ISOFORM LONG).
RC TISSUE=Umbilical vein;
RX PubMed=1692830;
RA Gougos A., Letarte M.;
RT "Primary structure of endoglin, an RGD-containing glycoprotein of
RT human endothelial cells.";
RL J. Biol. Chem. 265:8361-8364(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 122-378.
RX PubMed=7894484; DOI=10.1038/ng1294-345;
RA McAllister K.A., Grogg K.M., Johnson D.W., Gallione C.J.,
RA Baldwin M.A., Jackson C.E., Helmbold E.A., Markel D.S., McKinnon W.C.,
RA Murrell J., McCormick M.K., Pericak-Vance M.A., Heutink P.,
RA Oostra B.A., Haitjema T., Westerman C.J., Porteous M.E.,
RA Guttmacher A.E., Letarte M., Marchuk D.A.;
RT "Endoglin, a TGF-beta binding protein of endothelial cells, is the
RT gene for hereditary haemorrhagic telangiectasia type 1.";
RL Nat. Genet. 8:345-351(1994).
RN [6]
RP INTERACTION WITH TCTEX1D4.
RX PubMed=16982625; DOI=10.1074/jbc.M608614200;
RA Meng Q.-J., Lux A., Holloschi A., Li J., Hughes J.M.X., Foerg T.,
RA McCarthy J.E.G., Heagerty A.M., Kioschis P., Hafner M., Garland J.M.;
RT "Identification of Tctex2beta, a novel dynein light chain family
RT member that interacts with different transforming growth factor-beta
RT receptors.";
RL J. Biol. Chem. 281:37069-37080(2006).
RN [7]
RP INTERACTION WITH ARRB2.
RX PubMed=17540773; DOI=10.1074/jbc.M700176200;
RA Lee N.Y., Blobe G.C.;
RT "The interaction of endoglin with beta-arrestin2 regulates
RT transforming growth factor-beta-mediated ERK activation and migration
RT in endothelial cells.";
RL J. Biol. Chem. 282:21507-21517(2007).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-134, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [9]
RP FUNCTION, AND INTERACTION WITH GDF2.
RX PubMed=21737454; DOI=10.1074/jbc.M111.260133;
RA Castonguay R., Werner E.D., Matthews R.G., Presman E., Mulivor A.W.,
RA Solban N., Sako D., Pearsall R.S., Underwood K.W., Seehra J.,
RA Kumar R., Grinberg A.V.;
RT "Soluble endoglin specifically binds bone morphogenetic proteins 9 and
RT 10 via its orphan domain, inhibits blood vessel formation, and
RT suppresses tumor growth.";
RL J. Biol. Chem. 286:30034-30046(2011).
RN [10]
RP INTERACTION WITH GDF2.
RX PubMed=22347366; DOI=10.1371/journal.pone.0029948;
RA Alt A., Miguel-Romero L., Donderis J., Aristorena M., Blanco F.J.,
RA Round A., Rubio V., Bernabeu C., Marina A.;
RT "Structural and functional insights into endoglin ligand recognition
RT and binding.";
RL PLoS ONE 7:E29948-E29948(2012).
RN [11]
RP FUNCTION.
RX PubMed=23300529; DOI=10.1371/journal.pone.0050920;
RA Nolan-Stevaux O., Zhong W., Culp S., Shaffer K., Hoover J.,
RA Wickramasinghe D., Ruefli-Brasse A.;
RT "Endoglin requirement for BMP9 signaling in endothelial cells reveals
RT new mechanism of action for selective anti-endoglin antibodies.";
RL PLoS ONE 7:E50920-E50920(2012).
RN [12]
RP VARIANT HHT1 192-ARG--PRO-198 DEL, AND VARIANT MET-5.
RX PubMed=9245986;
RA Shovlin C.L., Hughes J.M.B., Scott J., Seidman C.E., Seidman J.G.;
RT "Characterization of endoglin and identification of novel mutations in
RT hereditary hemorrhagic telangiectasia.";
RL Am. J. Hum. Genet. 61:68-79(1997).
RN [13]
RP VARIANT HHT1 ASP-160.
RX PubMed=9157574;
RA Yamaguchi H., Azuma H., Shigekiyo T., Inoue H., Saito S.;
RT "A novel missense mutation in the endoglin gene in hereditary
RT hemorrhagic telangiectasia.";
RL Thromb. Haemost. 77:243-247(1997).
RN [14]
RP VARIANTS HHT1 VAL-52; ARG-53; CYS-149 AND PRO-306.
RX PubMed=9554745;
RX DOI=10.1002/(SICI)1098-1004(1998)11:4<286::AID-HUMU6>3.3.CO;2-2;
RA Gallione C.J., Klaus D.J., Yeh E.Y., Stenzel T.T., Xue Y.,
RA Anthony K.B., McAllister K.A., Baldwin M.A., Berg J.N., Lux A.,
RA Smith J.D., Vary C.P.H., Craigen W.J., Westermann C.J.J., Warner M.L.,
RA Miller Y.E., Jackson C.E., Guttmacher A.E., Marchuk D.A.;
RT "Mutation and expression analysis of the endoglin gene in hereditary
RT hemorrhagic telangiectasia reveals null alleles.";
RL Hum. Mutat. 11:286-294(1998).
RN [15]
RP VARIANTS HHT1 VAL-52; ARG-53; CYS-149 AND PRO-221.
RX PubMed=10545596; DOI=10.1093/hmg/8.12.2171;
RA Pece-Barbara N., Cymerman U., Vera S., Marchuk D.A., Letarte M.;
RT "Expression analysis of four endoglin missense mutations suggests that
RT haploinsufficiency is the predominant mechanism for hereditary
RT hemorrhagic telangiectasia type 1.";
RL Hum. Mol. Genet. 8:2171-2181(1999).
RN [16]
RP VARIANT HHT1 VAL-413.
RX PubMed=10982033; DOI=10.1007/s004390050008;
RA Gallione C.J., Scheessele E.A., Reinhardt D., Duits A.J., Berg J.N.,
RA Westermann C.J.J., Marchuk D.A.;
RT "Two common endoglin mutations in families with hereditary hemorrhagic
RT telangiectasia in the Netherlands Antilles: evidence for a founder
RT effect.";
RL Hum. Genet. 107:40-44(2000).
RN [17]
RP VARIANT HHT1 ARG-53.
RX PubMed=10625079; DOI=10.1203/00006450-200001000-00008;
RA Cymerman U., Vera S., Pece-Barbara N., Bourdeau A., White R.I. Jr.,
RA Dunn J., Letarte M.;
RT "Identification of hereditary hemorrhagic telangiectasia type 1 in
RT newborns by protein expression and mutation analysis of endoglin.";
RL Pediatr. Res. 47:24-35(2000).
RN [18]
RP VARIANTS HHT1 PRO-8; PHE-49; ARG-107; CYS-207 DEL; THR-263;
RP ARG-232-233-THR DEL; ILE-263 DEL; SER-412 AND MET-504.
RX PubMed=15024723; DOI=10.1002/humu.20017;
RG French Rendu-Osler network;
RA Lesca G., Plauchu H., Coulet F., Lefebvre S., Plessis G., Odent S.,
RA Riviere S., Leheup B., Goizet C., Carette M.-F., Cordier J.-F.,
RA Pinson S., Soubrier F., Calender A., Giraud S.;
RT "Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary
RT hemorrhagic telangiectasia in France.";
RL Hum. Mutat. 23:289-299(2004).
RN [19]
RP VARIANTS HHT1 PRO-221; ILE-263 DEL AND LEU-615.
RX PubMed=15712270; DOI=10.1002/humu.9311;
RA Kuehl H.K.A., Caselitz M., Hasenkamp S., Wagner S., El-Harith E.-H.A.,
RA Manns M.P., Stuhrmann M.;
RT "Hepatic manifestation is associated with ALK1 in hereditary
RT hemorrhagic telangiectasia: identification of five novel ALK1 and one
RT novel ENG mutations.";
RL Hum. Mutat. 25:320-320(2005).
CC -!- FUNCTION: Major glycoprotein of vascular endothelium. Involved in
CC the regulation of angiogenesis. May play a critical role in the
CC binding of endothelial cells to integrins and/or other RGD
CC receptors. Acts as TGF-beta coreceptor and is involved in the TGF-
CC beta/BMP signaling cascade. Required for GDF2/BMP9 signaling
CC through SMAD1 in endothelial cells and modulates TGF-beta1
CC signaling through SMAD3.
CC -!- SUBUNIT: Homodimer that forms a heteromeric complex with the
CC signaling receptors for transforming growth factor-beta: TGFBR1
CC and/or TGFBR2. It is able to bind TGF-beta 1, and 3 efficiently
CC and TGF-beta 2 less efficiently. Interacts with TCTEX1D4.
CC Interacts with ARRB2. Interacts with GDF2.
CC -!- INTERACTION:
CC P08648:ITGA5; NbExp=4; IntAct=EBI-2834630, EBI-1382311;
CC P05556:ITGB1; NbExp=3; IntAct=EBI-2834630, EBI-703066;
CC P01137:TGFB1; NbExp=2; IntAct=EBI-2834630, EBI-779636;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P17813-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P17813-2; Sequence=VSP_004233;
CC -!- TISSUE SPECIFICITY: Endoglin is restricted to endothelial cells in
CC all tissues except bone marrow.
CC -!- DISEASE: Hereditary hemorrhagic telangiectasia 1 (HHT1)
CC [MIM:187300]: Autosomal dominant multisystemic vascular dysplasia,
CC characterized by recurrent epistaxis, muco-cutaneous
CC telangiectases, gastro-intestinal hemorrhage, and pulmonary
CC (PAVM), cerebral (CAVM) and hepatic arteriovenous malformations;
CC all secondary manifestations of the underlying vascular dysplasia.
CC Although the first symptom of HHT1 in children is generally nose
CC bleed, there is an important clinical heterogeneity. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ENG";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ENGID40452ch9q34.html";
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DR EMBL; X72012; CAA50891.1; -; mRNA.
DR EMBL; AL157935; CAI12604.1; -; Genomic_DNA.
DR EMBL; AL162586; CAI12604.1; JOINED; Genomic_DNA.
DR EMBL; AL162586; CAI39764.1; -; Genomic_DNA.
DR EMBL; AL157935; CAI39764.1; JOINED; Genomic_DNA.
DR EMBL; CH471090; EAW87702.1; -; Genomic_DNA.
DR EMBL; J05481; AAA35800.1; -; mRNA.
DR EMBL; U37439; AAC63386.1; -; Genomic_DNA.
DR EMBL; AF036969; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; U37447; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; AF036970; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; U37446; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; U37445; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; AF036971; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; U37442; AAC63386.1; JOINED; Genomic_DNA.
DR EMBL; U37441; AAC63386.1; JOINED; Genomic_DNA.
DR PIR; S50831; S50831.
DR RefSeq; NP_000109.1; NM_000118.3.
DR RefSeq; NP_001108225.1; NM_001114753.2.
DR RefSeq; NP_001265067.1; NM_001278138.1.
DR UniGene; Hs.76753; -.
DR ProteinModelPortal; P17813; -.
DR DIP; DIP-6246N; -.
DR IntAct; P17813; 8.
DR MINT; MINT-4529566; -.
DR STRING; 9606.ENSP00000362299; -.
DR PhosphoSite; P17813; -.
DR DMDM; 3041681; -.
DR PaxDb; P17813; -.
DR PRIDE; P17813; -.
DR DNASU; 2022; -.
DR Ensembl; ENST00000344849; ENSP00000341917; ENSG00000106991.
DR Ensembl; ENST00000373203; ENSP00000362299; ENSG00000106991.
DR GeneID; 2022; -.
DR KEGG; hsa:2022; -.
DR UCSC; uc004bsj.5; human.
DR CTD; 2022; -.
DR GeneCards; GC09M130577; -.
DR HGNC; HGNC:3349; ENG.
DR HPA; CAB000096; -.
DR HPA; HPA011862; -.
DR MIM; 131195; gene.
DR MIM; 187300; phenotype.
DR neXtProt; NX_P17813; -.
DR Orphanet; 329971; Generalized juvenile polyposis/juvenile polyposis coli.
DR Orphanet; 774; Rendu-Osler-Weber disease.
DR PharmGKB; PA27785; -.
DR eggNOG; NOG46276; -.
DR HOGENOM; HOG000112346; -.
DR HOVERGEN; HBG005573; -.
DR InParanoid; P17813; -.
DR KO; K06526; -.
DR OMA; HCDLQPV; -.
DR OrthoDB; EOG70S754; -.
DR PhylomeDB; P17813; -.
DR ChiTaRS; ENG; human.
DR GeneWiki; Endoglin; -.
DR GenomeRNAi; 2022; -.
DR NextBio; 8193; -.
DR PRO; PR:P17813; -.
DR ArrayExpress; P17813; -.
DR Bgee; P17813; -.
DR CleanEx; HS_ENG; -.
DR Genevestigator; P17813; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0072563; C:endothelial microparticle; IEA:Ensembl.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0070022; C:transforming growth factor beta receptor homodimeric complex; IC:BHF-UCL.
DR GO; GO:0048185; F:activin binding; TAS:BHF-UCL.
DR GO; GO:0005534; F:galactose binding; IDA:BHF-UCL.
DR GO; GO:0005539; F:glycosaminoglycan binding; IDA:BHF-UCL.
DR GO; GO:0005072; F:transforming growth factor beta receptor, cytoplasmic mediator activity; IDA:BHF-UCL.
DR GO; GO:0005024; F:transforming growth factor beta-activated receptor activity; IDA:BHF-UCL.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:BHF-UCL.
DR GO; GO:0034713; F:type I transforming growth factor beta receptor binding; ISS:BHF-UCL.
DR GO; GO:0005114; F:type II transforming growth factor beta receptor binding; ISS:BHF-UCL.
DR GO; GO:0048844; P:artery morphogenesis; ISS:BHF-UCL.
DR GO; GO:0030509; P:BMP signaling pathway; TAS:BHF-UCL.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0060326; P:cell chemotaxis; IMP:BHF-UCL.
DR GO; GO:0003273; P:cell migration involved in endocardial cushion formation; IEA:Ensembl.
DR GO; GO:0022009; P:central nervous system vasculogenesis; IMP:BHF-UCL.
DR GO; GO:0001300; P:chronological cell aging; IEA:Ensembl.
DR GO; GO:0070483; P:detection of hypoxia; IDA:BHF-UCL.
DR GO; GO:0022617; P:extracellular matrix disassembly; IMP:BHF-UCL.
DR GO; GO:0001947; P:heart looping; ISS:BHF-UCL.
DR GO; GO:0030336; P:negative regulation of cell migration; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0051001; P:negative regulation of nitric-oxide synthase activity; IMP:BHF-UCL.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IMP:BHF-UCL.
DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:BHF-UCL.
DR GO; GO:0001569; P:patterning of blood vessels; ISS:BHF-UCL.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0003084; P:positive regulation of systemic arterial blood pressure; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0030155; P:regulation of cell adhesion; TAS:BHF-UCL.
DR GO; GO:0042127; P:regulation of cell proliferation; TAS:BHF-UCL.
DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; IDA:HGNC.
DR GO; GO:0048745; P:smooth muscle tissue development; ISS:BHF-UCL.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0048845; P:venous blood vessel morphogenesis; ISS:BHF-UCL.
DR GO; GO:0042060; P:wound healing; IMP:BHF-UCL.
DR InterPro; IPR001507; ZP_dom.
DR Pfam; PF00100; Zona_pellucida; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Angiogenesis; Cell adhesion; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 25
FT CHAIN 26 658 Endoglin.
FT /FTId=PRO_0000021156.
FT TOPO_DOM 26 586 Extracellular (Potential).
FT TRANSMEM 587 611 Helical; (Potential).
FT TOPO_DOM 612 658 Cytoplasmic (Potential).
FT REGION 26 337 Required for interaction with EGL.
FT MOTIF 399 401 Cell attachment site (Potential).
FT COMPBIAS 336 576 Ser/Thr-rich.
FT MOD_RES 646 646 Phosphoserine; by TGFBR1 (By similarity).
FT MOD_RES 649 649 Phosphoserine; by TGFBR1 (By similarity).
FT CARBOHYD 88 88 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 102 102 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 121 121 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 134 134 N-linked (GlcNAc...).
FT CARBOHYD 307 307 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 619 658 SPSKREPVVAVAAPASSESSSTNHSIGSTQSTPCSTSSMA
FT -> EYPRPPQ (in isoform Short).
FT /FTId=VSP_004233.
FT VARIANT 5 5 T -> M (in dbSNP:rs35400405).
FT /FTId=VAR_005192.
FT VARIANT 8 8 L -> P (in HHT1).
FT /FTId=VAR_026774.
FT VARIANT 49 49 V -> F (in HHT1).
FT /FTId=VAR_026775.
FT VARIANT 52 52 G -> V (in HHT1).
FT /FTId=VAR_005193.
FT VARIANT 53 53 C -> R (in HHT1).
FT /FTId=VAR_005194.
FT VARIANT 107 107 L -> R (in HHT1).
FT /FTId=VAR_026776.
FT VARIANT 149 149 W -> C (in HHT1).
FT /FTId=VAR_005195.
FT VARIANT 160 160 A -> D (in HHT1).
FT /FTId=VAR_009120.
FT VARIANT 192 198 Missing (in HHT1).
FT /FTId=VAR_005196.
FT VARIANT 207 207 Missing (in HHT1).
FT /FTId=VAR_026777.
FT VARIANT 221 221 L -> P (in HHT1).
FT /FTId=VAR_009121.
FT VARIANT 232 233 Missing (in HHT1).
FT /FTId=VAR_026778.
FT VARIANT 263 263 I -> T (in HHT1).
FT /FTId=VAR_026780.
FT VARIANT 263 263 Missing (in HHT1).
FT /FTId=VAR_026779.
FT VARIANT 306 306 L -> P (in HHT1).
FT /FTId=VAR_005197.
FT VARIANT 366 366 D -> H (in dbSNP:rs1800956).
FT /FTId=VAR_014764.
FT VARIANT 412 412 C -> S (in HHT1).
FT /FTId=VAR_026781.
FT VARIANT 413 413 G -> V (in HHT1).
FT /FTId=VAR_037140.
FT VARIANT 504 504 V -> M (in HHT1; dbSNP:rs116330805).
FT /FTId=VAR_026782.
FT VARIANT 615 615 S -> L (in HHT1).
FT /FTId=VAR_026783.
FT CONFLICT 14 14 L -> G (in Ref. 4; AA sequence).
FT CONFLICT 122 130 SSLVTFQEP -> FQPGHLPRA (in Ref. 5).
SQ SEQUENCE 658 AA; 70578 MW; 49CA2CE013298D17 CRC64;
MDRGTLPLAV ALLLASCSLS PTSLAETVHC DLQPVGPERG EVTYTTSQVS KGCVAQAPNA
ILEVHVLFLE FPTGPSQLEL TLQASKQNGT WPREVLLVLS VNSSVFLHLQ ALGIPLHLAY
NSSLVTFQEP PGVNTTELPS FPKTQILEWA AERGPITSAA ELNDPQSILL RLGQAQGSLS
FCMLEASQDM GRTLEWRPRT PALVRGCHLE GVAGHKEAHI LRVLPGHSAG PRTVTVKVEL
SCAPGDLDAV LILQGPPYVS WLIDANHNMQ IWTTGEYSFK IFPEKNIRGF KLPDTPQGLL
GEARMLNASI VASFVELPLA SIVSLHASSC GGRLQTSPAP IQTTPPKDTC SPELLMSLIQ
TKCADDAMTL VLKKELVAHL KCTITGLTFW DPSCEAEDRG DKFVLRSAYS SCGMQVSASM
ISNEAVVNIL SSSSPQRKKV HCLNMDSLSF QLGLYLSPHF LQASNTIEPG QQSFVQVRVS
PSVSEFLLQL DSCHLDLGPE GGTVELIQGR AAKGNCVSLL SPSPEGDPRF SFLLHFYTVP
IPKTGTLSCT VALRPKTGSQ DQEVHRTVFM RLNIISPDLS GCTSKGLVLP AVLGITFGAF
LIGALLTAAL WYIYSHTRSP SKREPVVAVA APASSESSST NHSIGSTQST PCSTSSMA
//

MIM 131195
*RECORD*
*FIELD* NO
131195
*FIELD* TI
*131195 ENDOGLIN; ENG
;;CD105
*FIELD* TX

DESCRIPTION

Endoglin (ENG), also called CD105, is a homodimeric membrane
read moreglycoprotein primarily associated with human vascular endothelium. It is
also found on bone marrow proerythroblasts, activated monocytes, and
lymphoblasts in childhood leukemia. Endoglin is a component of the
transforming growth factor-beta (TGFB) receptor complex and binds TGFB1
(190180) with high affinity (Rius et al., 1998).

CLONING

Gougos and Letarte (1990) isolated a cDNA encoding ENG lacking a leader
sequence from an endothelial cell cDNA library. By screening a leukemia
cell cDNA library, Bellon et al. (1993) obtained full-length cDNAs
encoding 2 variants of ENG. Both contain a 25-amino acid leader peptide,
followed by 561 residues in the extracellular portion and a 25-amino
acid transmembrane sequence. However, the long variant has a 47-amino
acid cytoplasmic tail, while the tail of the short variant contains only
14 residues. Flow cytometric and immunoprecipitation analyses indicated
high expression of both the 160- and 170-kD disulfide-linked homodimer
ENG variants at the cell surface. RT-PCR analysis detected expression of
both variants on activated monocytes, endothelial cells, and placenta,
with the long form being predominant.

GENE FUNCTION

Bellon et al. (1993) found that both isoforms of ENG could bind TGFB1.

Rius et al. (1998) cloned and characterized the promoter region of the
ENG gene. They showed that the endoglin promoter exhibits inducibility
in the presence of TGFB1, suggesting possible therapeutic treatments in
HHT1 (187300) patients, in which the expression level of the normal
endoglin allele might not reach the threshold required for its function.

Grisanti et al. (2004) analyzed endoglin expression in choroidal
neovascular membranes (CNVMs) surgically excised from eyes with
age-related macular degeneration (ARMD; see 153800). Endoglin expression
was increased in the endothelial cells of CNVMs but was rarely
associated with a concomitant expression of the proliferation marker
Ki-67 (176741). The authors concluded that the elevated expression of
endoglin in the surgically excised CNVMs suggested a persisting
postmitotic activation in an advanced stage of neovascular tissue.

Hereditary hemorrhagic telangiectasia (see 187300) and cerebral
cavernous malformations (see 116860) are disorders involving disruption
of normal vascular morphogenesis. The autosomal dominant mode of
inheritance in both of these disorders suggested to Marchuk et al.
(2003) that their underlying genes might regulate critical aspects of
vascular morphogenesis. The authors summarized the roles of these genes,
endoglin, KRIT1 (604214), and ALK1 (ACVRL1; 601284), in the genetic
control of angiogenesis.

Lebrin et al. (2004) found that mouse endothelial cells lacking endoglin
did not grow because Tgfb/Alk1 signaling was reduced and Tgfb/Alk5
(190181) signaling was increased. Surviving cells adapted to the
imbalance and proliferated by downregulating Alk5 expression. Lebrin et
al. (2004) concluded that endoglin has a role in the balance of ALK1 and
ALK5 signaling to regulate endothelial cell proliferation.

GIPC1 (605072) is a scaffolding protein that regulates cell surface
receptor expression and trafficking. Using predominantly embryonic mouse
endothelial cell lines, Lee et al. (2008) showed that endoglin and Gipc
interacted directly. The interaction enhanced TGF-beta-1-induced
phosphorylation of Smad1 (601595)/Smad5 (603110)/Smad8 (SMAD9; 603295),
increased a Smad1/Smad5/Smad8-responsive promoter, and inhibited
endothelial cell migration.

Chen et al. (2009) found increased levels of soluble endoglin in
vascular surgical specimens from 33 patients with arteriovenous
malformations of the brain (BAVM; 108010) compared to similar specimens
from 8 epileptic patients. However, there was no difference in
expression of membrane-bound endoglin and no difference in plasma
soluble endoglin between BAVM patients and controls. Transduction of
soluble endoglin in mouse brain resulted in the formation of abnormal
and dysplastic capillary structures, and was associated with increased
levels of matrix metalloproteinase activity and oxidative radicals. Chen
et al. (2009) suggested that soluble endoglin may play a role in the
formation of sporadic BAVM by acting as a decoy receptor, resulting in
inhibition of TGF-beta signaling and functional haploinsufficiency of
ENG, as observed in patients with HHT1.

Muenzner et al. (2010) found that CEA (114890)-binding bacteria
colonized the urogenital tract of CEA transgenic mice, but not of
wildtype mice, by suppressing exfoliation of mucosal cells. CEA binding
triggered de novo expression of the transforming growth factor receptor
CD105, changing focal adhesion composition and activating beta-1
integrins (135630). Muenzner et al. (2010) concluded that this
manipulation of integrin inside-out signaling promotes efficient mucosal
colonization and represents a potential target to prevent or cure
bacterial infections.

Wang et al. (2013) identified upregulation of Lrg1 (611289) in the
transcriptome of retinal microvessels isolated from mouse models of
retinal disease that exhibit vascular pathology. The authors showed that
in the presence of transforming growth factor-beta-1 (TGFB1; 190180),
Lrg1 is mitogenic to endothelial cells and promotes angiogenesis. Mice
lacking Lrg1 developed a mild retinal vascular phenotype but exhibited a
significant reduction in pathologic ocular angiogenesis. Lrg1 bound
directly to the Tgf-beta accessory receptor endoglin, which, in the
presence of TGF-beta-1, resulted in promotion of the proangiogenic
Smad1/5/8 signaling pathway. Lrg1 antibody blockade inhibited this
switch and attenuated angiogenesis. Wang et al. (2013) concluded that
these studies revealed that LRG1 is a regulator of angiogenesis that
mediates its effect by modulating TGF-beta signaling.

GENE STRUCTURE

McAllister et al. (1994) concluded that the coding region of the ENG
gene contains 14 exons. They thought it likely that there are additional
exons.

MAPPING

By Southern blot analysis of DNA from human-hamster somatic cell
hybrids, Fernandez-Ruiz et al. (1993) mapped the ENG gene to human
chromosome 9. By fluorescence in situ hybridization, they regionalized
the assignment to 9q34-qter, distal to the breakpoint of the
Philadelphia chromosome. The mouse endoglin locus is genetically
inseparable from the adenylate kinase-1 locus (Pilz et al., 1994). Thus,
the ENG gene is probably located in the 9q34.1 region in the human.
Qureshi et al. (1995) mapped the mouse ENG homolog to chromosome 2, near
the nebulin locus (161650).

MOLECULAR GENETICS

In a panel of 68 DNA samples from probands of unrelated hereditary
hemorrhagic telangiectasia (HHT1) families, most of whom were members of
kindreds with pulmonary arteriovenous malformations (PAVMs), McAllister
et al. (1994) identified mutations in the ENG gene in 3 affected
individuals.

Shovlin et al. (1997) identified 7 novel mutations in the ENG gene in 8
families. Two of the mutations (a termination codon in exon 4 and a
large genomic deletion extending 3-prime of intron 8) did not produce a
stable ENG transcript in lymphocytes. Five other mutations (2 donor
splice site mutations (e.g., 131195.0004) and 3 deletions) produced
altered mRNAs that were predicted to encode markedly truncated ENG
proteins. These data suggested that the molecular mechanism by which ENG
mutations cause HHT is haploinsufficiency. Furthermore, because the
clinical manifestation of disease in these 8 families was similar,
Shovlin et al. (1997) hypothesized that phenotypic variation of HHT is
not related to a particular ENG mutation. They found that 41% (23 of 56)
of HHT patients with ENG mutations had pulmonary arteriovenous
malformations, whereas a significantly smaller fraction, 14% (5 of 35),
of HHT patients in whom linkage analyses indicated non-ENG mutations had
PAVMs (P less than 0.01).

In a newborn from a family with HHT, Pece et al. (1997) identified a
novel endoglin splice site mutation (131195.0005) that resulted in
skipping of exon 3 and the expression of a mutant protein missing 47
amino acids but with an intact transmembrane region. This mutant protein
was considered particularly suited for testing the dominant-negative
model as it is more likely to be expressed at the cell surface than
truncated ones. However, it was detectable only by metabolic labeling,
did not form heterodimers with normal endoglin, and did not reach the
cell surface. In activated monocytes from 3 patients with known
truncations, no mutant protein could be detected. However, when cDNA
corresponding to 2 other HHT1 endoglin truncations were overexpressed in
COS-1 cells, mutant proteins could be detected intracellularly, were not
secreted, and did not form heterodimers with wildtype endoglin. Thus,
Pece et al. (1997) concluded that mutant endoglin in HHT patients
appears to be only transiently expressed and not to represent a dominant
negative. The data strongly suggested that a reduced level of functional
endoglin leads to the abnormalities seen in HHT1 patients. In these
studies, expression of normal and mutant endoglin proteins was analyzed
in umbilical vein endothelial cells from the baby and in activated
monocytes from the affected father. In both samples, only normal dimeric
endoglin (160 kD) was observed at the cell surface, at 50% of control
levels. Despite an intact transmembrane region, mutant protein was
detectable only by metabolic labeling, as an intracellular homodimer of
130 kD.

Gallione et al. (1998) described 11 novel ENG mutations in HHT kindreds,
which included missense and splice site mutations. In 2 unrelated
families, they identified a T-to-C transition in the ATG initiation
codon, which converted the initiator methionine to threonine. Non-ATG
codons can initiate at 3 to 5% of normal translation levels when flanked
by specific consensus sequences (Kozak, 1989). However, the sequence
context of the specific mutation in the 2 HHT families did not fit the
consensus for even such reduced initiation. The first potential in-frame
initiation codon was within exon 5. If protein synthesis was initiated
at this position, the product would lack the signal peptide for proper
membrane trafficking, as well as 30% of the N-terminal residues. This
initiation codon mutation appeared to be a classic null allele that
eliminated the translation of the endoglin protein.

Pece-Barbara et al. (1999) stated that to that date 29 different
mutations had been reported in HHT1 in the endoglin gene and 18 distinct
mutations had been described for the ALK1 gene (601284), which underlies
type 2 hereditary hemorrhagic telangiectasia (HHT2; 600376).

Although a dominant-negative model of endoglin dysfunction was initially
proposed for HHT1, Pece et al. (1997) observed a mutant protein
(131195.0005) that was transiently expressed intracellularly both in
monocytes from an HHT1 patient and in human umbilical vein endothelial
cells (HUVECs) from the child of the patient. As the cell
surface-expressed protein was still able to associate with the TGF-beta
receptor complex, this indicated that it is the reduction in the level
of surface endoglin, rather than interference by mutant protein, that is
involved in the generation of HHT1. The description of 3 null mutations
where mRNA transcripts were undetectable again suggested that endoglin
haploinsufficiency is the molecular basis for HHT1. The observation that
every HHT1 family so far studied was found to have a distinct mutation
and that mutations of all types are distributed throughout the gene was
again consistent with a haploinsufficiency model. Pece-Barbara et al.
(1999) studied 4 missense mutations and found that none was
significantly expressed at the surface of COS-1 transfectants. Thus,
although these 4 HHT1 missense mutations led to transient intracellular
species, they cannot interfere with normal endoglin function.

To determine whether mechanisms other than haploinsufficiency might be
involved in HHT1, Lux et al. (2000) investigated 8 different mutations
in the ENG gene. Missense mutants were expressed but apparently
misfolded, and most showed no cell surface expression. When coexpressed
with wildtype endoglin, missense mutants were able to dimerize with
normal endoglin protein and were transported to the cell surface. The
protein product of one truncation mutation was unable to dimerize with
normal endoglin, and likely acts through haploinsufficiency. On the
contrary, the delta-GC frameshift mutation (131195.0003) was able to
dimerize with normal endoglin, and likely acts in a dominant-negative
fashion by interfering with protein processing or cell surface
expression. Thus, the authors concluded that either dominant-negative
protein interactions or haploinsufficiency can cause HHT1.

To maximize the detection of potential mutant proteins, Paquet et al.
(2001) utilized pulse-chase experiments to analyze the expression of
large truncation mutations and missense mutations in cells from HHT1
patients with 13 unique mutations. All HHT1 mutants analyzed, although
expressed to various degrees in COS-1 cells, were either undetectable,
present at low levels as transient intracellular forms, or expressed as
partially glycosylated precursors in endogenous cells. The mutants did
not form heterodimers with normal endoglin and did not interfere with
its normal trafficking to the cell surface, further supporting the
haploinsufficiency model.

In COS-1 transfected cells, Abdalla et al. (2000) determined that ALK1
was found in the TGFB1 and -B3 (190230) receptor complexes in
association with endoglin and TGFBR2 (190182), but not in activin (see
147290) receptor complexes containing endoglin. In HUVEC, ALK1 was not
detectable in TGFB1 or -B3 receptor complexes. However, in the absence
of ligand, ALK1 and endoglin interactions were observed by
immunoprecipitation/Western blot in HUVEC from normal as well as HHT1
and HHT2 patients. The authors hypothesized that a transient association
between ALK1 and endoglin is required at a critical level to ensure
vessel wall integrity.

Cymerman et al. (2003) optimized a quantitative multiplex PCR (QMPCR)
analysis to efficiently detect deletions and insertions in the ENG gene
in HHT1 patients from 18 families. They reported 17 novel mutations, of
which 6 were detected by QMPCR. Review of 80 HHT1 families (62
previously reported and the 18 described) indicated that 10% would not
have been resolved by sequencing and that an additional 25% could be
revealed by QMPCR performed before sequencing. Thus the use of QMPCR can
accelerate genetic screening for HHT1 and resolve mutations affecting
whole exons.

Lastella et al. (2003) detected 4 novel and 1 previously reported
mutation in the ENG gene in Italian patients with HHT.

In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding
sequences of the ENG and ALK1 genes. Germline mutations were identified
in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in
ALK1.

In 7 Danish HHT families, Brusgaard et al. (2004) identified a novel
nonsense mutation (131195.0009) in the ENG gene, which they
characterized as a founder mutation.

Abdalla and Letarte (2006) tabulated the known ENG mutations identified
in hereditary hemorrhagic telangiectasia.

Bayrak-Toydemir et al. (2006) identified mutations in 26 (76%) of 34
kindreds with HHT. Fourteen (54%) mutations were in the ENG gene,
consistent with HHT1, and 12 (46%) were in the ACVRL1 gene, consistent
with HHT2.

Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated
German patients with HHT. Among these mutations, 11 of 13 ENG mutations
and 12 of 17 ACVRL1 mutations were not previously reported in the
literature. Analysis of genotype/phenotype correlations was consistent
with a more common frequency of PAVMs in patients with ENG mutations
(HHT1).

Sweet et al. (2005) sequenced the ENG gene in 14 patients with juvenile
polyposis syndrome (JPS; 174900) who were negative for mutation in the 2
known JPS genes, SMAD4 (600993) and BMPR1A (601299), and identified
germline missense mutations in the ENG gene in 2 patients, respectively.
The mutations were not found in 105 North American controls. In 3 of 31
patients with JPS who were negative for mutations in the SMAD4 and
BMPR1A genes, Howe et al. (2007) identified 2 different nonsynonymous
substitutions that had been previously identified as polymorphisms in
patients with HTT. Howe et al. (2007) stated that their findings did not
confirm the suggestion that the ENG gene predisposes for JPS.

In a German woman with clinical features of HHT and negative direct
sequencing results, Shoukier et al. (2008) identified a deletion of exon
4 of the ENG gene using quantitative real-time polymerase chain reaction
(QRT-PCR) and confirmed by multiplex ligation-dependent probe
amplification (MLPA).

ANIMAL MODEL

Li et al. (1999) generated mice deficient for endoglin using homologous
recombination. Eng +/- mice had normal life expectancy, fertility, and
gross appearance. Eng -/- mice died by embryonic day 11.5. At embryonic
day 10.5, Eng -/- mice were 3 times smaller than Eng +/+ mice and had
fewer somites. The Eng -/- embryos exhibited an absence of vascular
organization and the presence of multiple pockets of red blood cells on
the surface of the yolk sac. Epithelial marker expression was not
disrupted in Eng -/- mice. There was persistence of an immature
perineural vascular plexus, indicating a failure of endothelial
remodeling in Eng -/- embryos. At embryonic day 10.5, the cardiac tube
did not complete rotation and was associated with a serosanguinous
pericardial effusion. By embryonic day 10.5, the major vessels including
the dorsal aortae, intersomitic vessels, branchial arches, and carotid
arteries were atretic and disorganized in Eng -/- embryos. There was
also poor vascular smooth muscle cell formation at both embryonic days
9.5 and 10.5. These vascular smooth muscle cell abnormalities preceded
the differences in endothelial organization. In contrast to mice lacking
TGF-beta, vasculogenesis was unaffected. Li et al. (1999) concluded that
their results demonstrated that endoglin is essential for angiogenesis
and suggest a pathogenic mechanism for HHT1.

Bourdeau et al. (1999) likewise generated mice lacking 1 or both copies
of the endoglin gene. Endoglin null embryos died at gestational day
10.0-10.5 due to defects in vessel and heart development. Vessel
formation appeared normal until hemorrhage occurred in yolk sacs and
embryos. The primitive vascular plexus of the yolk sac failed to mature
into defined vessels, and vascular channels dilated and ruptured.
Internal bleeding was seen in the peritoneal cavity, implying fragile
vessels. Heart development was arrested at day 9.0, and the
atrioventricular canal endocardium failed to undergo mesenchymal
transformation and cushion-tissue formation. The data suggested that
endoglin is critical for both angiogenesis and heart valve formation.
Some heterozygotes showed signs of HHT, such as telangiectases or
recurrent nosebleeds. In this murine model of HHT, it appeared that
epigenetic factors and modifier genes, some of which are present in the
129/Ola strain, which shows expressing heterozygotes, contribute to
disease heterogeneity.

Lebrin et al. (2010) showed that treatment of Eng +/- with thalidomide
normalized inappropriate vessel formation and promoted pericyte and
mural cell activation and vessel maturation via increased expression of
Pdgfb (190040). In vitro studies of mouse tissue showed that thalidomide
stimulated the recruitment of mural cells to the vessel branches,
resulting in a stabilization of blood vessels and a rescue of vessel
wall defects. Treatment reduced nosebleed frequency in 6 of 7 humans
with HHT, and reduced the duration of nosebleeds in 3 of 4 for whom data
were available.

*FIELD* AV
.0001
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, TYR277TER

In a patient with hereditary hemorrhagic telangiectasia (187300),
McAllister et al. (1994) found a C-to-G transition at nucleotide
position 831 resulting in conversion of tyrosine-277 to a termination
codon. The truncated protein resulting from this mutation would comprise
only half of the extracellular domain and lack the membrane-spanning and
cytoplasmic domains.

.0002
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, 39-BP DEL

In a patient with hereditary hemorrhagic telangiectasia (187300),
McAllister et al. (1994) found deletion of 39 nucleotides (882 to 920)
in exon 7, removing 13 amino acids from the protein and altering the
first amino acid (position 307) in a potential N-linked glycosylation
site. The mutation segregated only with affected members of the
3-generation family.

.0003
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, 2-BP DEL, FS, TER

In affected members of a family with hereditary hemorrhagic
telangiectasia (187300), McAllister et al. (1994) found a 2-bp deletion
(nucleotides 1553 and 1554) that created a MaeIII restriction site and
caused a frameshift with a premature termination codon 8 amino acids
beyond the deletion. The predicted truncated protein would lack the
membrane-spanning and cytoplasmic domains of endoglin.

.0004
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, IVS3DS, A-G, +4

One of 7 novel mutations in the endoglin gene found by Shovlin et al.
(1997) in patients with HHT1 (187300) was a deletion of exon 3 due to an
A-to-G transition at position 4 of the donor splice site of intron 3.

.0005
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, IVS3DS, G-A, +1, EX3DEL

In a patient with HHT1 (187300), Pece et al. (1997) detected a splice
site mutation of the ENG gene resulting in in-frame deletion of exon 3
from the transcript and a truncated polypeptide.

.0006
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, 2T-C, MET1THR

In 2 unrelated families with HHT1 (187300), Gallione et al. (1998)
identified a missense mutation of the initiation codon. A T-to-C
transition converted ATG (met) to ACG (thr). Since flanking sequences
did not satisfy the consensus sequences found by Kozak (1989) to permit
initiation from non-ATG codons and the first potential in-frame
initiation codon was within exon 5, Gallione et al. (1998) predicted
that this would function as a classic null mutation.

.0007
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, GLY413VAL

In the Leeward Islands of the Netherlands Antilles where the prevalence
of HHT (187300) is perhaps the highest of any geographic region,
Gallione et al. (2000) found that 1 of 2 common mutations was a missense
mutation in exon 9a of the ENG gene: a G-to-T transversion at nucleotide
1238, resulting in a gly413-to-val substitution.

.0008
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, IVS1DS, G-A, +1

In 7 of 10 families in the Netherlands Antilles with HHT (187300),
Gallione et al. (2000) found a splice site mutation in the ENG gene: a
G-to-A transition at position +1 of intron 1.

.0009
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ENG, TYR120TER

In 7 of 25 Danish families with HHT (187300), Brusgaard et al. (2004)
identified a 360C-A transversion in exon 3 of the ENG gene, resulting in
a tyr120-to-ter (Y120X) substitution. Brusgaard et al. (2004) thought
the Y120X founder mutation may have been introduced around 350 years
earlier.

*FIELD* RF
1. Abdalla, S. A.; Letarte, M.: Hereditary haemorrhagic telangiectasia:
current views on genetics and mechanisms of disease. J. Med. Genet. 43:
97-110, 2006.

2. Abdalla, S. A.; Pece-Barbara, N.; Vera, S.; Tapia, E.; Paez, E.;
Bernabeu, C.; Letarte, M.: Analysis of ALK-1 and endoglin in newborns
from families with hereditary hemorrhagic telangiectasia type 2. Hum.
Molec. Genet. 9: 1227-1237, 2000.

3. Bayrak-Toydemir, P.; McDonald, J.; Markewitz, B.; Lewin, S.; Miller,
F.; Chou, L.-S.; Gedge, F.; Tang, W.; Coon, H.; Mao, R.: Genotype-phenotype
correlation in hereditary hemorrhagic telangiectasia: mutations and
manifestations. Am. J. Med. Genet. 140A: 463-470, 2006.

4. Bellon, T.; Corbi, A.; Lastres, P.; Cales, C.; Cebrian, M.; Vera,
S.; Cheifetz, S.; Massague, J.; Letarte, M.; Bernabeu, C.: Identification
and expression of two forms of the human transforming growth factor-beta-binding
protein endoglin with distinct cytoplasmic regions. Europ. J. Immun. 23:
2340-2345, 1993.

5. Bourdeau, A.; Dumont, D. J.; Letarte, M.: A murine model of hereditary
hemorrhagic telangiectasia. J. Clin. Invest. 104: 1343-1351, 1999.

6. Brusgaard, K.; Kjeldsen, A. D.; Poulsen, L.; Moss, H.; Vase, P.;
Rasmussen, K.; Kruse, T. A.; Horder, M.: Mutations in endoglin and
in activin receptor-like kinase 1 among Danish patients with hereditary
haemorrhagic telangiectasia. Clin. Genet. 66: 556-561, 2004.

7. Chen, Y.; Hao, Q.; Kim, H.; Su, H.; Letarte, M.; Karumanchi, S.
A.; Lawton, M. T.; Barbaro, N. M.; Yang, G.-Y.; Young, W. L.: Soluble
endoglin modulates aberrant cerebral vascular remodeling. Ann. Neurol. 66:
19-27, 2009.

8. Cymerman, U.; Vera, S.; Karabegovic, A.; Abdalla, S.; Letarte,
M.: Characterization of 17 novel endoglin mutations associated with
hereditary hemorrhagic telangiectasia. Hum. Mutat. 21: 482-492,
2003.

9. Fernandez-Ruiz, E.; St. Jacques, S.; Bellon, T.; Letarte, M.; Bernabeu,
C.: Assignment of the human endoglin gene (END) to 9q34-qter. Cytogenet.
Cell Genet. 64: 204-207, 1993.

10. Gallione, C. J.; Klaus, D. J.; Yeh, E. Y.; Stenzel, T. T.; Xue,
Y.; Anthony, K. B.; McAllister, K. A.; Baldwin, M. A.; Berg, J. N.;
Lux, A.; Smith, J. D.; Vary, C. P. H.; Craigen, W. J.; Westermann,
C. J. J.; Warner, M. L.; Miller, Y. E.; Jackson, C. E.; Guttmacher,
A. E.; Marchuk, D. A.: Mutation and expression analysis of the endoglin
gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum.
Mutat. 11: 286-294, 1998.

11. Gallione, C. J.; Scheessele, E. A.; Reinhardt, D.; Duits, A. J.;
Berg, J. N.; Westermann, C. J. J.; Marchuk, D. A.: Two common endoglin
mutations in families with hereditary hemorrhagic telangiectasia in
the Netherlands Antilles: evidence for a founder effect. Hum. Genet. 107:
40-44, 2000.

12. Gougos, A.; Letarte, M.: Primary structure of endoglin, an RGD-containing
glycoprotein of human endothelial cells. J. Biol. Chem. 265: 8361-8364,
1990.

13. Grisanti, S.; Canbek, S.; Kaiserling, E.; Adam, A.; Lafaut, B.;
Gelisken, F.; Szurman, P.; Henke-Fahle, S.; Oficjalska-Mlynczak, J.;
Bartz-Schmidt, K. U.: Expression of endoglin in choroidal neovascularization. Exp.
Eye Res. 78: 207-213, 2004.

14. Howe, J. R.; Haidle, J. L.; Lal, G.; Bair, J.; Song, C.; Pechman,
B.; Chinnathambi, S.; Lynch, H. T.: ENG mutations in MADH4/BMPR1A
mutation negative patients with juvenile polyposis. (Letter) Clin.
Genet. 71: 91-92, 2007.

15. Kozak, M.: Context effects and inefficient initiation at non-AUG
codons in eucaryotic cell-free translation systems. Molec. Cell.
Biol. 9: 5073-5080, 1989.

16. Lastella, P.; Sabba, C.; Lenato, G. M.; Resta, N.; Lattanzi, W.;
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17. Lebrin, F.; Goumans, M.-J.; Jonker, L.; Carvalho, R. L. C.; Valdimarsdottir,
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18. Lebrin, F.; Srun, S.; Raymond, K.; Martin, S.; van den Brink,
S.; Freitas, C.; Breant, C.; Mathivet, T.; Larrivee, B.; Thomas, J.-L.;
Arthur, H. M.; Westermann, C. J. J.; Disch, F.; Mager, J. J.; Snijder,
R. J.; Eichmann, A.; Mummery, C. L.: Thalidomide stimulates vessel
maturation and reduces epistaxis in individuals with hereditary hemorrhagic
telangiectasia. Nature Med. 16: 420-428, 2010.

19. Lee, N. Y.; Ray, B.; How, T.; Blobe, G. C.: Endoglin promotes
transforming growth factor beta-mediated Smad 1/5/8 signaling and
inhibits endothelial cell migration through its association with GIPC. J.
Biol. Chem. 283: 32527-32533, 2008.

20. Lesca, G.; Plauchu, H.; Coulet, F.; Lefebvre, S.; Plessis, G.;
Odent, S.; Riviere, S.; Leheup, B.; Goizet, C.; Carette, M.-F.; Cordier,
J.-F.; Pinson, S.; Soubrier, F.; Calender, A.; Giraud, S.: Molecular
screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia
in France. Hum. Mutat. 23: 289-299, 2004.

21. Li, D. Y.; Sorensen, L. K.; Brooke, B. S.; Urness, L. D.; Davis,
E. C.; Taylor, D. G.; Boak, B. B.; Wendel, D. P.: Defective angiogenesis
in mice lacking endoglin. Science 284: 1534-1537, 1999.

22. Lux, A.; Gallione, C. J.; Marchuk, D. A.: Expression analysis
of endoglin missense and truncation mutations: insights into protein
structure and disease mechanisms. Hum. Molec. Genet. 9: 745-755,
2000.

23. Marchuk, D. A.; Srinivasan, S.; Squire, T. L.; Zawistowski, J.
S.: Vascular morphogenesis: tales of two syndromes. Hum. Molec.
Genet. 12(R1): R97-R112, 2003.

24. McAllister, K. A.; Grogg, K. M.; Johnson, D. W.; Gallione, C.
J.; Baldwin, M. A.; Jackson, C. E.; Helmbold, E. A.; Markel, D. S.;
McKinnon, W. C.; Murrell, J.; McCormick, M. K.; Pericak-Vance, M.
A.; Heutink, P.; Oostra, B. A.; Haitjema, T.; Westerman, C. J. J.;
Porteous, M. E.; Guttmacher, A. E.; Letarte, M.; Marchuk, D. A.:
Endoglin, a TGF-beta binding protein of endothelial cells, is the
gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet. 8:
345-351, 1994.

25. Muenzner, P.; Bachmann, V.; Zimmermann, W.; Hentschel, J.; Hauck,
C. R.: Human-restricted bacterial pathogens block shedding of epithelial
cells by stimulating integrin activation. Science 329: 1197-1201,
2010.

26. Paquet, M.-E.; Pece-Barbara, N.; Vera, S.; Cymerman, U.; Karabegovic,
A.; Shovlin, C.; Letarte, M.: Analysis of several endoglin mutants
reveals no endogenous mature or secreted protein capable of interfering
with normal endoglin function. Hum. Molec. Genet. 10: 1347-1357,
2001.

27. Pece, N.; Vera, S.; Cymerman, U.; White, R. I., Jr.; Wrana, J.
L.; Letarte, M.: Mutant endoglin in hereditary hemorrhagic telangiectasia
type 1 is transiently expressed intracellularly and is not a dominant
negative. J. Clin. Invest. 100: 2568-2579, 1997.

28. Pece-Barbara, N.; Cymerman, U.; Vera, S.; Marchuk, D. A.; Letarte,
M.: Expression analysis of four endoglin missense mutations suggests
that haploinsufficiency is the predominant mechanism for hereditary
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29. Pilz, A.; Woodward, K.; Peters, J.; Povey, S.; Abbott, C.: Comparative
mapping of 38 human chromosome 9 loci in the laboratory mouse. (Abstract) Ann.
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30. Qureshi, S. T.; Gros, P.; Letarte, M.; Malo, D.: The murine endoglin
gene (Eng) maps to chromosome 2. Genomics 26: 165-166, 1995.

31. Rius, C.; Smith, J. D.; Almendro, N.; Langa, C.; Botella, L. M.;
Marchuk, D. A.; Vary, C. P. H.; Bernabeu, C.: Cloning of the promoter
region of human endoglin, the target gene for hereditary hemorrhagic
telangiectasia type 1. Blood 92: 4677-4690, 1998.

32. Shoukier, M.; Teske, U.; Weise, A.; Engel, W.; Argyriou, L.:
Characterization of five novel large deletions causing hereditary
haemorrhagic telangiectasia. Clin. Genet. 73: 320-330, 2008.

33. Shovlin, C. L.; Hughes, J. M. B.; Scott, J.; Seidman, C. E.; Seidman,
J. G.: Characterization of endoglin and identification of novel mutations
in hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet. 61:
68-79, 1997.

34. Sweet, K.; Willis, J.; Zhou, X.-P.; Gallione, C.; Sawada, T.;
Alhopuro, P.; Khoo, S. K.; Patocs, A.; Martin, C.; Bridgeman, S.;
Heinz, J.; Pilarski, R.; Lehtonen, R.; Prior, T. W.; Frebourg, T.;
Teh, B. T.; Marchuk, D. A.; Aaltonen, L. A.; Eng, C.: Molecular classification
of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294:
2465-2473, 2005.

35. Wang, X.; Abraham, S.; McKenzie, J. A. G.; Jeffs, N.; Swire, M.;
Tripathi, V. B.; Luhmann, U. F. O.; Lange, C. A. K.; Zhai, Z.; Arthur,
H. M.; Bainbridge, J. W. B.; Moss, S. E.; Greenwood, J.: LRG1 promotes
angiogenesis by modulating endothelial TGF-beta signalling. Nature 499:
306-311, 2013. Note: Erratum: Nature 501: 578 only, 2013.

36. Wehner, L.-E.; Folz, B. J.; Argyriou, L.; Twelkemeyer, S.; Teske,
U.; Geisthoff, U. W.; Werner, J. A.; Engel, W.; Nayernia, K.: Mutation
analysis in hereditary haemorrhagic telangiectasia in Germany reveals
11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin. Genet. 69:
239-245, 2006.

*FIELD* CN
Ada Hamosh - updated: 9/20/2013
Cassandra L. Kniffin - updated: 1/25/2011
Ada Hamosh - updated: 10/27/2010
Cassandra L. Kniffin - updated: 5/27/2010
Patricia A. Hartz - updated: 4/21/2009
Cassandra L. Kniffin - updated: 9/16/2008
Marla J. F. O'Neill - updated: 3/9/2007
Cassandra L. Kniffin - updated: 4/27/2006
Cassandra L. Kniffin - updated: 3/21/2006
Victor A. McKusick - updated: 3/9/2006
Patricia A. Hartz - updated: 7/6/2005
Victor A. McKusick - updated: 3/31/2005
George E. Tiller - updated: 3/3/2005
Jane Kelly - updated: 7/30/2004
Victor A. McKusick - updated: 5/5/2004
Victor A. McKusick - updated: 7/10/2003
Victor A. McKusick - updated: 6/11/2003
George E. Tiller - updated: 11/13/2001
Paul J. Converse - updated: 8/17/2001
Victor A. McKusick - updated: 9/12/2000
George E. Tiller - updated: 7/7/2000
George E. Tiller - updated: 4/25/2000
Victor A. McKusick - updated: 12/7/1999
Victor A. McKusick - updated: 11/19/1999
Ada Hamosh - updated: 5/27/1999
Victor A. McKusick - updated: 2/1/1999
Victor A. McKusick - updated: 4/29/1998
Victor A. McKusick - updated: 12/3/1997
Victor A. McKusick - updated: 8/20/1997
Alan F. Scott - updated: 9/26/1995

*FIELD* CD
Victor A. McKusick: 11/3/1993

*FIELD* ED
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carol: 11/17/1993
carol: 11/3/1993

MIM 187300
*RECORD*
*FIELD* NO
187300
*FIELD* TI
#187300 TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER;
HHT
;;OSLER-RENDU-WEBER DISEASE;;
read moreORW DISEASE
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 1, INCLUDED; HHT1, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because hereditary hemorrhagic
telangiectasia type 1 (HHT1) is caused by heterozygous mutation in the
gene encoding endoglin (ENG; 131195) on chromosome 9q34.

DESCRIPTION

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant
vascular dysplasia leading to telangiectases and arteriovenous
malformations of skin, mucosa, and viscera. Epistaxis and
gastrointestinal bleeding are frequent complications of mucosal
involvement. Visceral involvement includes that of the lung, liver, and
brain. The most frequent form of hereditary hemorrhagic telangiectasia
maps to the long arm of chromosome 9.

- Genetic Heterogeneity of Hereditary Hemorrhagic Telangiectasia

See also HHT2 (600376), which is caused by mutations in the ALK1 gene
(ACVRL1; 601284) on chromosome 12q. HHT3 (601101) has been mapped to
chromosome 5q31 and HHT4 (610655) to chromosome 7p14.

See also juvenile polyposis/HHT syndrome (175050), caused by mutation in
the SMAD4 gene (600993).

CLINICAL FEATURES

HHT is highly penetrant; Plauchu et al. (1989) in a series of 384
patients found at least 1 manifestation in 97%, while Porteous et al.
(1992) found complete penetrance by 40 years of age in a series of 35
British families with 98 affected members. Sixty-two percent of these
were clinically affected by age 16, with epistaxes being the presenting
feature in 90% of cases. Aassar et al. (1991) found that the mean age of
onset of epistaxis in HHT was 12 years with more than 90% becoming
manifest before 21 years. Blood loss from the nasal mucosa may become
severe. Telangiectases also occur on the mucosal surface of the tongue
(where bleeding may prove difficult to control), lips, face,
conjunctiva, ears and fingers. Plauchu et al. (1989) noted facial
involvement in 33% and lesions on the hands or wrists of 41% of their
patients

Porteous et al. (1992) found significant gastrointestinal hemorrhage in
16% of patients with half of these requiring transfusion. The
preponderance of upper GI involvement may have reflected the reliance on
upper GI endoscopy.

By angiographic methods, various types of visceral angiodysplasias have
been demonstrated (Halpern et al., 1968). These include arterial
aneurysm, arteriovenous communication including discrete arteriovenous
fistula, conglomerate masses of angiectasia, phlebectasia, and angioma.
Pulmonary arteriovenous malformations (PAVMs) are a significant cause of
morbidity. Some are sufficiently large to cause heart failure leading to
polycythaemia and clubbing. Paradoxical emboli may cause infarction or
abscess formation in the brain and elsewhere. Vase et al. (1985)
reported PAVMs in 20% of their series. Plauchu et al. (1989) found PAVMs
in 4.6% with an age range of 1 to 78 years. In the study of Porteous et
al. (1992) 13 (23%) of those who had undergone chest radiography had a
visible PAVM; 4 suffered embolic complications, 3 cerebral abscesses,
and one a stroke. In one 17-year-old, 50% of the circulating volume was
passing through a single PAVM. Reyes-Mujica et al. (1988) described HHT
in a 23-month-old girl who died of massive pulmonary hemorrhage. There
were no skin lesions but vascular anomalies of varying severity were
found in the tongue, esophagus, liver, kidney, central nervous system,
ovaries, spleen, and lymph nodes. Before death, the child had 15
episodes of hemoptysis and 2 of epistaxis. The parents, by contrast, had
no evidence of the disease but 1 grandfather had died after bleeding
from the mouth following physical exertion. Dines et al. (1974) reviewed
63 cases of pulmonary arteriovenous fistula seen at the Mayo Clinic; HHT
was recognized in 38 (60%).

Cirrhosis of the liver may occur; Plauchu et al. (1989) found liver
involvement in 27 patients (8%); 17 of these had cirrhosis, which was
the cause of death in 5. Michaeli et al. (1968) described a 47-year-old
woman with HHT disease and hepatic portacaval shunts of sufficient
magnitude to cause repeated episodes of encephalopathy. The liver was
not scarred. Nikolopoulos et al. (1988) raised the question of familial
tendency to hepatic involvement in HHT. They described 2 brothers with
intrahepatic arteriovenous shunts of sufficient size to cause
hyperdynamic circulation, leading to cirrhosis; the mother and 3
maternal uncles died of cirrhosis with rupture of esophageal varices.
Members of the previous generation also had a history of hyperdynamic
circulation. Selmaier et al. (1993) described the case of a 50-year-old
woman with heart failure resulting from calcified hemangiomatosis of the
liver with a high shunt volume. Saxena et al. (1998) reported the case
of a 43-year-old woman who received a transplant for end-stage liver
disease due to HHT and fibropolycystic liver disease. The liver showed
extensive vascular malformations of arteries and veins, as well as
telangiectasia and fibrosis. In addition, there were cystically dilated
ducts containing inspissated bile and extensive von Meyenburg complexes.
The case raised the question of a possible relationship between
polycystic liver disease (174050) and HHT. (A von Meyenburg complex
consists of clusters of small bile ducts occurring in polycystic livers,
separate from the portal areas.)

In the liver, the vascular abnormalities of HHT are associated with
marked fibrosis and/or cirrhosis. Weik and Greiner (1999) found hepatic
manifestations of HHT in 4 women and 1 man (51 to 63 years of age)
presenting initially with slight disturbances of liver function. In 3
patients, progressive liver insufficiency developed.

Garcia-Tsao et al. (2000) described the clinical findings and results of
hemodynamic, angiographic, and imaging studies in 19 patients with HHT
and symptomatic liver involvement. Ages ranged from 34 to 74 years in
the 14 women and 5 men. All but 1 had a hyperdynamic circulation
(cardiac index, 4.2 to 7.3 liters per minute per square meter of
body-surface area). In 8 patients, the clinical findings were consistent
with the presence of high-output heart failure. Manifestations of portal
hypertension such as ascites or variceal bleeding were present in 6
patients. Manifestations of biliary disease, such as an elevated
alkaline phosphatase level and abnormalities on bile duct imaging, were
present in 5 patients. One of these patients died after an unsuccessful
attempt at liver transplantation.

Cooke (1986) described renal arteriovenous malformations in a patient
with episodic hematuria and renal colic due to clots.

Telangiectases may occur in the bladder though Plauchu et al. (1989)
found only 2 symptomatic patients among their 324 cases. Kurnik and
Heymann (1989) described 3-vessel coronary artery ectasia without
evidence of atherosclerosis in a 51-year-old man with classic HHT
disease. This manifestation had not previously been described although
ectasia of other vessels such as intraabdominal ones is well known. In a
study of 20 patients with HHT, Brant et al. (1989) found conjunctival
telangiectases in 7 and retinal vascular malformations in 2. Visual loss
from the intraocular lesions is a rare complication. Bloody tears
sometimes occur in patients with conjunctival telangiectases and
bleeding from the eyes may also result from the backing up of blood in
the lacrimal duct during epistaxis with packing of the nostrils.

Most of the neurologic morbidity is related to emboli but vascular
malformations may occur; Guillen et al. (1991) found 1 individual, in a
Mexican family with 15 affected members, who needed surgical treatment
for a cerebral lesion, while 3 of the patients seen by Porteous et al.
(1992) had symptomatic cerebral lesions. In the latter report, 46.3% of
patients with no known CNS pathology described visual symptoms
suggestive of migrainous aura in the absence of headache and nausea
compared to 5.7% of controls. Steele et al. (1993) investigated migraine
prevalence in 58 British adult HHT gene carriers without known
neurologic deficits; 40 carriers of the gene for familial adenomatous
polyposis (FAP; 175100) were used as controls. They found that 50% of
the HHT carriers fulfill diagnostic criteria for migraine with aura, 4
times the disease control group and 10 times the estimated population
prevalence. White had observed this symptom separately and noted that
headaches improved in patients who had undergone balloon occlusion of
PAVMs (White et al., 1988). This raises the possibility of vasoactive
substances which would normally be removed in the pulmonary vascular bed
reaching the central nervous system, though if this is the explanation
it would suggest that almost half of gene carriers have pulmonary
involvement. Another factor may be occult intracranial AVMs; 6 to 8% of
HHT patients with PAVMs also have intracranial lesions (Romain et al.,
1978).

Fulbright et al. (1998) reviewed brain magnetic resonance imaging (MRI)
of 184 consecutive patients with HHT. Catheter angiography was performed
in 17 patients in whom cerebrovascular malformations (CVMs) were
detected on MRIs. They found 63 CVMs in 42 patients. Classic
arteriovenous malformations (n = 10) had a conspicuous network of
vessels with flow voids and enlarged adjacent pial vessels. Apparent
venous malformations (n = 5) were best seen after administration of
contrast material as a prominent vessel coursing through normal brain
parenchyma. Indeterminate vascular malformations (n = 48) had a spectrum
of appearances characterized by variable combinations of heterogeneous
signal intensity, enhancement, or hemosiderin. Angiography in 17
patients revealed 47 CVMs. Forty-six were arteriovenous malformations
(AVMs), including 25 CVMs not seen with MRI and 21 CVMs that by MR
criteria included 8 AVMs and 13 indeterminate vascular malformations.
Angiography confirmed 1 venous malformation seen with MRI but failed to
detect 3 indeterminate lesions revealed by MRI. Thus, MRI revealed a CVM
prevalence of 23% (42 of 184). Most CVMs (48 of 63) had an atypical
appearance for vascular malformations on MR images. Angiographic
correlation suggests that MRI underestimates the prevalence of CVMs and
that the majority of indeterminate CVMs, despite their variable MRI
appearance, are AVMs.

Kopel and Lage (1998) described a 37-year-old woman with HHT who
developed a large pericardial effusion with cardiac tamponade.
Pericardiocentesis yielded a large amount of hemorrhagic pericardial
fluid. Because of recurrent cardiac tamponade, the patient underwent
partial surgical pericardial excision. Histologic examination of the
pericardium showed vascular dysplasia with signs of hemorrhage and
inflammation.

Canzonieri et al. (2014) examined the gastrointestinal tract of
consecutive HHT patients to assess distribution, number, size, and type
of telangiectases in relation to genotype. Twenty-two patients (13 men;
mean age 59 +/- 9 years) were analyzed, 7 with HHT1, 13 with HHT2
(600376), and 2 undefined. Gastrointestinal telangiectases were
identified in 86% of HHT1 patients and in 77% of HHT2 patients.

- Reviews

Guttmacher et al. (1995) reviewed all aspects of HHT. They emphasized
that it is important for those affected to be aware of their diagnosis
and its implications and to inform health care providers of their
codition. Guttmacher et al. (1995) announced that educational materials
for patients and providers are available from the HHT Foundation
International, Inc.

Haitjema et al. (1996) provided a review. Marchuk et al. (1998) reported
on a 1997 workshop on hereditary hemorrhagic telangiectasia.

Govani and Shovlin (2009) reviewed the molecular and genetic basis of
hereditary hemorrhagic telangiectasia and discussed approaches for
diagnosis and clinical management.

INHERITANCE

HHT disease is inherited as an autosomal dominant trait. Snyder and Doan
(1944) reported a possible instance of homozygosity, 2 affected parents
had a stillborn offspring who had extensive angiomatous malformation of
the viscera.

In a large Arab family in the Sahara, Muller et al. (1978) found 87
cases in 6 generations. Because of the extensive consanguinity in the
kindred, a person considered to be homozygous was identified. In the
case of 4 couples indicated in the pedigree, both partners were
affected. The son of one such couple had a total of 13 children by 4
different wives. All the wives were unaffected; all the children were
affected. According to the Bayes theory, the probability of homozygosity
was estimated to be 0.99975. The father, who was the presumed homozygote
and also the proband, had severe but no exceptionally unusual
manifestations of the disease.

MAPPING

Using microsatellite markers in a study of 2 extensively affected
families, McDonald et al. (1993) showed that the HHT gene maps to 9q.
D9S164 showed a combined maximum lod score of 4.39 at a recombination
fraction of 0.14, and D9S103 showed a combined maximum lod score of 3.53
at a recombination fraction of 0.11. The probable location of the HHT
gene, otherwise symbolized ORW, is 9q33-q34.1. McDonald et al. (1994)
estimated that the closest marker, D9S65, is within 1 cM of the gene; it
showed a combined lod score of 11.41 with HHT. Shovlin et al. (1994)
independently assigned HHT to 9q.

MOLECULAR GENETICS

McAllister et al. (1994) examined endoglin (ENG; 131195), a transforming
growth factor-beta (TGF-beta) binding protein, as a candidate gene for
HHT because of its chromosomal location, expression pattern, and
function. They identified mutations in the ENG gene in 3 affected
individuals from different families. This was the first human disease
defined as due to a mutation in a member of the TGF-beta receptor
complex. Primary pulmonary hypertension (PPH1; 178600) is another
autosomal dominant inherited vascular disorder that is caused by a
defect in BMPR2 (600799), which is a member of the TGF-beta signaling
pathway.

In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding
sequences of the ENG and ALK1 genes. Germline mutations were identified
in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in
ALK1.

Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated
German patients with HHT. Thirteen mutations were in the ENG gene,
consistent with HHT1, and 17 mutations were in the ACVRL1 gene,
consistent with HHT2. Analysis of genotype/phenotype correlations was
consistent with a more common frequency of PAVMs in patients with HHT1.

Bossler et al. (2006) described the results of mutation analysis on a
consecutive series of 200 individuals undergoing clinical genetic
testing for HHT. A total of 127 probands were found, with sequence
changes consisting of 103 unique alterations, 68 of which were novel. In
addition 8 intragenic rearrangements in the ENG gene (131195), and 2 in
ACVRL1 gene (601284) were identified. Surprisingly, almost 50% of the
individuals with a single symptom were found to have a significant
sequence alteration; 3 of these reported only nosebleeds.

In a German woman with clinical features of HHT and negative direct
sequencing results, Shoukier et al. (2008) identified a deletion of exon
4 of the ENG gene using quantitative real-time polymerase chain reaction
(QRT-PCR) and confirmed by multiplex ligation-dependent probe
amplification (MLPA).

- Exclusion Studies

Greenspan et al. (1995) excluded the COL5A1 gene as a candidate for HHT
mapping to chromosome 9q.

GENOTYPE/PHENOTYPE CORRELATIONS

Berg et al. (2003) performed a questionnaire-based study to delineate
phenotypic differences between HHT1 and HHT2, which are caused by
mutation in the ENG gene and ALK1 (601284) gene, respectively. The
questionnaires were completed by 83 patients with known mutations (49
had HHT1 and 34 had HHT2). Patients with HHT1 reported an earlier onset
of epistaxis and telangiectasis than those with HHT2. Pulmonary
arteriovenous malformations were reported only in the group of HHT1
patients.

Among 14 kindreds with HHT1 and 12 with HHT2 confirmed by genetic
analysis, Bayrak-Toydemir et al. (2006) found that HHT2 was associated
with later onset and more hepatic involvement than HHT1.

Letteboer et al. (2006) analyzed phenotype in relation to sex in 584
Dutch probands and affected family members with HHT1 and HHT2 confirmed
by genetic analysis. For the HHT1 group, they found a significantly
higher prevalence of PAVM and hepatic AVM in women than in men.

In a study of 268 Dutch patients with HHT1 and 130 Dutch patients with
HHT2, Letteboer et al. (2008) found that oral and nasal mucosal
telangiectases were present earlier in life in patients with HHT1
compared to patients with HHT2, whereas dermal lesions were more
frequent and appeared earlier in life in patients with HHT2. In both
groups, telangiectases of the nasal mucosa were present at a higher
prevalence and started to appear earlier in life than those of the oral
mucosa or dermal sites. The number of sites affected increased with age
in both groups. In patients with HHT1, more women than men had skin
telangiectases, particularly on the face. These results confirmed that
the frequency of AVMs differ between patients with HHT1 and HHT2, and
that these differences can be detected on physical examination.

HETEROGENEITY

Genetic heterogeneity was indicated by the results of linkage studies by
several groups. Shovlin et al. (1994) found one family that did not map
to 9q3. Porteous et al. (1994) pointed out that all of the previously
reported 9q34-linked families contained at least 1 affected member with
a symptomatic PAVM. Porteous et al. (1994) reported 4 families
apparently unlinked to 9q34 and with no evidence of PAVMs. In a study by
McAllister et al. (1994), 4 of 7 families gave a posterior probability
of more than 99% being of the linked type and 3 families appeared
unlinked to 9q34. They were impressed also by the absence of PAVMs in
the 3 9q3-unlinked families. In 3 unrelated families of Dutch origin,
Heutink et al. (1994) confirmed the linkage to 9q, and in a fourth
unrelated family in which 'considerably fewer pulmonary arteriovenous
malformations' were present, there was evidence for nonlinkage to this
region.

Cronstedt et al. (1982) observed the coexistence of HHT disease and
primary thrombocythemia (187950) in 2 patients, both men in their 70s.

The observation of a family with both type IIA von Willebrand disease
(VWF2A; see 613554) and HHT prompted Iannuzzi et al. (1991) to study
genetic linkage of the 2 conditions. No linkage was detected and the VWF
gene (613160) was ruled out as a candidate gene for HHT because of the
finding of segregation in linkage studies.

PATHOGENESIS

Braverman et al. (1990) reconstructed representative cutaneous
telangiectases by computer from serial 1- or 2-mm plastic embedded
sections. The earliest clinically detectable lesion was a focal
dilatation of postcapillary venules, which continued to enlarge and
eventually connect with dilated arterioles through capillaries. As the
vascular lesion increased in size, the capillary segments disappeared
and a direct arteriovenous communication was formed. This sequence of
events was associated with a perivascular mononuclear cell infiltrate in
which most of the cells were lymphocytes and a minority are
monocytes/macrophages by ultrastructural characteristics. The
telangiectatic lesions of scleroderma are also composed of dilated
postcapillary venules and also associated with perivascular infiltrates.
Cherry angiomas, however, which are produced by capillary loop
aneurysms, are not associated with infiltrates.

DIAGNOSIS

An important phenocopy is the CRST syndrome (calcinosis, Raynaud
syndrome, sclerodactyly, telangiectasia; 181750), a probable 'collagen
vascular disease.' The mucosal and cutaneous telangiectases are
indistinguishable from those of the hereditary disorder (Winterbauer,
1964). Conlon et al. (1978) described 2 families in which telangiectasia
like that of HHT disease occurred with von Willebrand disease. Other
families with combined von Willebrand disease and HHT disease were
described by Ramsay et al. (1976), Ahr et al. (1977), Hanna et al.
(1984), and Iannuzzi et al. (1991). Since the CRST syndrome is
occasionally familial (Frayha et al., 1977), a positive family history
is not a conclusive differentiating feature of HHT disease.

On behalf of the Scientific Advisory Board of the HHT Foundation
International, Inc., Shovlin et al. (2000) presented consensus clinical
diagnostic criteria. The 4 criteria (epistaxes, telangiectasia, visceral
lesions, and an appropriate family history) were carefully delineated.
They considered the HHT diagnosis to be definite if 3 criteria were
present. They suggested that a diagnosis of HHT cannot be established in
patients with only 2 criteria, but should be recorded as possible or
suspected in order to maintain a high index of clinical suspicion. If
fewer than 2 criteria are present, HHT is unlikely, although children of
affected individuals should be considered at risk in view of age-related
penetrance in this disorder. They pointed out that these criteria may be
refined as molecular diagnostic tests become available in the future.

Mager and Westermann (2000) used capillary microscopy to compare the
capillary pattern of the fingernail folds in 54 patients with confirmed
diagnoses of HHT and 40 healthy controls. Forty-five (83%) of the 54
patients with HHT had giant loops between the normal capillaries in the
nail fold and 2 patients had enlargement of the draining limb of the
capillary only. Seven patients (13%) had no vascular abnormalities in
the nail fold. Seven of 9 patients with HHT but without cutaneous
telangiectases had microvascular abnormalities. None of the volunteers
had vascular abnormalities. The difference between both groups was
significant (chi square, P less than 0.001). Mager and Westermann (2000)
concluded that capillary microscopy can be useful in diagnosing HHT,
especially in children with an affected parent and cases where there are
few or atypical telangiectases present.

CLINICAL MANAGEMENT

Flessa and Glueck (1977) recommended Enovid (a combination of a
progestogen and an estrogen) for control of severe nosebleeds. They
described experience with 9 patients of whom 1 was male. Vase (1981)
could demonstrate no benefit of estrogen therapy. Oral estrogen has been
found useful in controlling the frequency and severity of epistaxis
(Harrison, 1982). It improves the continuity of telangiectatic
endothelium and induces metaplasia of overlying epithelium (Menefee et
al., 1975). Haq et al. (1988) used danazol, a synthetic weak androgen,
with highly satisfactory results in a single patient, a 41-year-old man.

Aminocoporic acid, an antifibrinolytic drug, can reduce epistaxis in HHT
(Saba et al., 1994), but its effect is inconsistent (Korzenik et al.,
1994). Sabba et al. (2001) successfully treated 3 HHT patients with
tranexamic acid, another antifibrinolytic drug which is 10 times as
potent as aminocoporic acid and has a longer half-life. Klepfish et al.
(2001) reported successful use of topical tranexamic acid for severe
epistaxis in HHT.

White et al. (1988) reported embolotherapy of pulmonary arteriovenous
malformations in 67 patients with HHT. Eleven of the patients had been
discovered by means of family screening with measurements of arterial
blood gases and chest radiography. Hypoxemia in the upright position is
a clue to the presence of PAVMs. The AV fistulae are most often found in
the lower lobes.

Lee et al. (1997) reported the long-term results of transcatheter
embolotherapy of large pulmonary arteriovenous malformations in 221
consecutive patients, many of them with HHT, treated over a period of 18
years by a single physician, Robert I. White, Jr. The follow-up focused
particularly on 45 patients with 52 PAVMs supplied by feeding arteries 8
mm in diameter or larger. Of these 45 patients, 38 (84%) with 44 PAVMs
(85%) were cured by the first embolotherapy (mean follow-up, 4.7 years).
Acute periprocedural complications included self-limited pleurisy (31%),
angina secondary to air embolus (2%), and paradoxical embolization of a
device during deployment (4%). None of these events led to short- or
long-term sequelae. Seven patients (16%) had persistence of the PAVM,
attributable to recanalization in 4 patients and to interim accessory
artery growth in 3. Two of these patients presented with ischemic stroke
several years after the initial treatment. Eight persistent PAVMs were
re-treated successfully, 7 by a second procedure and 1 with a third
procedure (mean follow-up, 5.9 and 5.3 years, respectively). Thus,
embolotherapy was successful in a great majority of cases. Continued
patency due to recanalization or accessory artery growth was easily
detected and treated.

Bose et al. (2009) reported a 42-year-old man with a 3-generation family
history of HHT who presented with longstanding epistaxis, hemoptysis,
and a hemoglobin level half that of normal. After unsuccessful treatment
with oral and intravenous iron, he received 4 cycles over 8 weeks of an
anti-VEGF (see 192240) antibody, bevacizumab. After treatment, the
patient's episodes of epistaxis were fewer in number and of shorter
duration, and his hemoglobin level remained stable without transfusion.

Oosting et al. (2009) reported treatment with bevacizumab in a
55-year-old man with HHT who had intractable pain and frequent episodes
of pancreatitis related to pancreatic AVMs. The treatment immediately
stopped the patient's epistaxis, skin vascular signs became less
pronounced, and the frequency and severity of pancreatitis diminished to
the point where morphine and tube feeding could be discontinued. No
change in the volume of AVMs was observed on CT scan. Retornaz et al.
(2009) administered bevacizumab to a 65-year-old woman with HHT and
life-threatening, recurrent hemorrhage, for which she had received 27
blood transfusions over a 6-month period. After treatment, blood
transfusions were not required for 2 months; subsequently, hemorrhage
recurred but with a reduced need for blood transfusion. Bose et al.
(2009) noted that these cases provided further evidence of the efficacy
of bevacizumab in patients with HHT, with improvement in symptoms and
transfusion requirements without appreciable change in AVMs; they stated
that although there was no difference in the size of their patient's
pulmonary AVMs on CT scan before and after bevacizumab, he continued to
report symptomatic benefit more than a year after completing therapy.

Lebrin et al. (2010) found that treatment with thalidomide, which has
antiangiogenic activity, reduced nosebleed frequency in 6 of 7
individuals with HHT, and reduced the duration of nosebleeds in 3 of 4
for whom data were available. There were some side effects, including
constipation and drowsiness. In vitro studies of mouse tissue showed
that thalidomide stimulated the recruitment of mural cells to the vessel
branches, resulting in a stabilization of blood vessels. Studies in Eng
+/- mice also showed that thalidomide normalized inappropriate vessel
formation and promoted pericyte and mural cell activation and vessel
maturation via increased expression of Pdgfb (190040).

Brinkerhoff et al. (2011) described the long-term outcome of a patient
who received multiple repeat courses of intravenous bevacizumab, a
potent VEGF antagonist, for treatment of severe HHT. The patient was a
62-year-old male with severe HHT-related epistaxis who required blood
transfusions and intravenous iron therapy to maintain a baseline
hemoglobin level ranging from 5 to 7 grams per deciliter. Treatment with
4 intravenous infusions every 2 weeks resolved the epistaxis and
improved his hemoglobin level to 13 grams per deciliter. After 1 year
without treatment, he had a progressive relapse. Retreatment again
resulted in cessation of epistaxis and a concomitant rise in hemoglobin.
Subsequently a third course was required. In each case, there was a
favorable response and no adverse events.

POPULATION GENETICS

In a study of 18 families, Tuente (1964) estimated the frequency of the
condition to be 1 or 2 in 100,000. The mutation rate was estimated to be
2 x 10(-6) to 3 x 10(-6).

Porteous et al. (1992) asked all clinicians in the northern region of
England for information regarding their patients with HHT; 79 patients
were identified in a population of 3.1 million, giving a minimum point
prevalence of 1 in 39,216. Given the variable expression, the true
incidence is likely to be much higher than this figure.

Plauchu et al. (1980) found a concentration of HHT patients in Haut-Jura
in eastern France; 120 affected individuals from 42 families lived in a
300-km square area.

Bideau et al. (1992) reported that only 17.8% of the genes of
inhabitants of the Valserine valley of the French Jura could be traced
to the 'original population,' although persons affected with HHT disease
belonged to a subset of the population that had lived in the villages
for more than 10 generations. All patients in 85 sibships were related.
The smallest number of originator couples who lived at the beginning of
the 18th century amounted to 16; the unique originator may, therefore,
have lived approximately 4 generations earlier.

Guttmacher et al. (1994) suggested that the prevalence of HHT has been
underestimated at the level of 1 in 50,000 to 100,000 and that the
disorder has not received the attention it deserves from the medical
genetics community. He urged clinical geneticists and genetic counselors
to play an active role in making the diagnosis, coordinating care, and
providing genetic counseling. They estimated the minimal prevalence rate
of HHT in Vermont to be 1:16,500 and suggested that this frequency is
not atypical of rates elsewhere.

Dakeishi et al. (2002) estimated the population prevalence of HHT in the
Akita prefecture of northern Japan to be 1:5,000 to 1:8,000, roughly
comparable with those reported in European and U.S. populations, which
is contradictory to the traditional view that HHT is rare among Asians.

Westermann et al. (2003) studied HHT in the Afro-Caribbean population of
the Netherlands Antilles and found a point prevalence of 1 in 1,331
inhabitants older than 12 years, the highest known in the world.

HISTORY

Osler (1849-1919) described this disorder as a 'family form of recurring
epistaxis, associated with multiple telangiectases of the skin and
mucous membranes' (Osler, 1901). The only previous report he could find
was that of Rendu dated 1896. Because of his prominence as a physician
and author of a textbook, Osler 'put the disorder on the map.' F. Parkes
Weber (1863-1962), who pronounced his name in the Germanic manner even
though he was born in England and always lived there, described cases
later as part of a life-long interest in angiomas and other vascular
lesions (McKusick, 1963). The frequent eponymic sequence, although not
chronologically accurate, is perhaps justified by the contribution to
the nosology of the entity: Osler-Rendu-Weber (pronounced OHz-ler,
ren-DYU, and VAY-ber). Hanes (1909), then a medical resident at the
Johns Hopkins Hospital, wrote a rather comprehensive discussion of this
disorder, together with color illustrations of the lesions of the lips,
tongue, and face, and named the disorder 'hereditary hemorrhagic
telangiectasia.'

Christian (1949), who graduated from Johns Hopkins in 1900 during
Osler's time there, wrote as follows: 'At another of the dispensary
clinics it fell to my lot to demonstrate the case of a young man who
frequently had come to the dispensary, as well as been a patient several
times in the hospital wards. He was deeply jaundiced and had a large
liver and many angiectases in his nose, which bled frequently and
profusely. His condition had been diagnosed as Hanot's cirrhosis. His
brother, a little older, had the same disease. The patient had devised a
very simple way to control his nose bleeds: He took a thin rubber finger
cot, put into its end a small cork, through which passed a small glass
tube, and to the glass tube he had attached a bit of thin-walled rubber
tubing. He would insert the finger cot well into his bleeding nostril,
expand it by blowing through the rubber tubing and clamp off the tubing
between his teeth to keep the cot distended until its pressure stopped
the nosebleed. I had him demonstrate this to the section, while Dr.
Osler commented on how simple but ingenious methods might be useful to
the physician and patient....Dr. Osler had asked me to keep track of the
patient, to report on his visits to the dispensary and to make follow-up
visits at his home. At a later clinic Dr. Osler asked me how the patient
was, and I replied, 'I think he is about as usual. I visited him about
two weeks ago.' With this, Dr. Osler, to my embarrassment, dramatically
brought forth a tray containing a large liver and other organs, saying,
'Christian, he did not continue to do so well. Dr. MacCallum autopsied
him this morning.' That was the only liver showing Hanot's cirrhosis
that I ever saw. Obviously, it made a great impression on me, and for
the subsequent fifty years I have diligently sought for another patient
with similar cirrhosis of the liver, so far with no success.' The
description by Christian (1949) sounds much like that given by Osler
(1901) in his classic paper but the latter concerned a man from Kentucky
whom he first saw in 1896, who had no affected relatives and no sign of
liver disease, and who was still alive at the time of Osler's report.
Osler (1901) wrote: 'He sent a diagram of an ingenious arrangement. He
took a rubber finger-stall about three inches long, into which was tied
a small bit of rubber tubing, with a stop-cock at one end. He inserted
the finger-stall, relaxed, then put the tubing in his mouth, inflated
it, and turned the stop-cock.' The diagram was included in a letter
dated Dec. 16, 1898. In the fifth edition of his Principles and Practice
of Medicine (1904; p. 574), Osler wrote concerning Hanot hypertrophic
cirrhosis: 'Of four recent cases under my care, the ages were from
twenty to thirty-five. Two were brothers.' Hanot cirrhosis is a vague
entity at best. Did the 2 brothers in fact suffer from Osler's disease,
hereditary hemorrhagic telangiectasia (as it was designated by Hanes,
1909), which is known to be accompanied by cirrhosis?

Reported instances of familial epistaxis (e.g., Lane, 1916) probably
represented this disorder. Indeed, Osler (1901) entitled his original
report, 'A family form of recurring epistaxis.'

Fuchizaki et al. (2003) provided biographical information on the
individuals whose names are included in triple eponym Rendu-Osler-Weber.

A comment on semantics: The individual lesion in HHT is a telangiectasis
(pl., telangiectases); the process is telangiectasia. Multiple lesions
should not be referred to as 'telangiectasias.' One would use the latter
term only in a statement such as, 'Dr. William Bennett Bean was a
student of the telangiectasias.'

ANIMAL MODEL

Li et al. (1999) generated mice deficient for endoglin (131195) using
homologous recombination. Eng +/- mice had normal life expectancy,
fertility, and gross appearance. Eng -/- mice died by embryonic day
11.5. At embryonic day 10.5, Eng -/- mice were 3 times smaller than Eng
+/+ mice and had fewer somites. The Eng -/- embryos exhibited an absence
of vascular organization and the presence of multiple pockets of red
blood cells on the surface of the yolk sac. Epithelial marker expression
was not disrupted in Eng -/- mice. There was persistence of an immature
perineural vascular plexus, indicating a failure of endothelial
remodeling in Eng -/- embryos. At embryonic day 10.5, the cardiac tube
did not complete rotation and was associated with a serosanguinous
pericardial effusion. By embryonic day 10.5, the major vessels including
the dorsal aortae, intersomitic vessels, branchial arches, and carotid
arteries were atretic and disorganized in Eng -/- embryos. There was
also poor vascular smooth muscle cell formation at both embryonic days
9.5 and 10.5. These vascular smooth muscle cell abnormalities preceded
the differences in endothelial organization. In contrast to mice lacking
TGF-beta, vasculogenesis was unaffected. Li et al. (1999) concluded that
their results demonstrated that endoglin is essential for angiogenesis
and suggest a pathogenic mechanism for HHT1.

*FIELD* SA
Bacardi et al. (1971); Baker (1980); Bergqvist et al. (1962); Bideau
et al. (1980); Burckhardt et al. (1973); Chandler (1965); Chernelch
et al. (1969); Childers et al. (1967); Daly and Schiller (1976); Davis
and Smith (1971); Feizi (1972); Foggie (1928); Harkonen (1981);
Harrison (1970); Hodgson et al. (1959); Kjellberg et al. (1983);
McAllister et al. (1994); McCaffrey et al. (1977); McCue et al. (1984);
Mirra and Arnold (1973); Nyman (1977); Rewane (1983); Rowley et
al. (1970); Saunders (1960); Schuster (1937); Tedesco et al. (1975);
Terry et al. (1980); Terry et al. (1983); Thomas and Carty (1974);
Trell et al. (1972); Whicker and Lake (1972)
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*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Conjunctival telangiectases;
[Nose];
Spontaneous, recurrent epistaxis (onset childhood);
Nasal mucosa telangiectases;
[Mouth];
Lip telangiectases;
Tongue telangiectases;
Palate telangiectases

CARDIOVASCULAR:
[Heart];
Right-to-left shunt;
High-output congestive heart failure;
[Vascular];
Arterial aneurysm;
Venous varicosities;
Arteriovenous fistulas of celiac and mesenteric vessels

RESPIRATORY:
Dyspnea;
[Lung];
Pulmonary arteriovenous malformation (PAVM), especially lower lobes;
Cyanosis

ABDOMEN:
[Liver];
Cirrhosis;
Hepatic arteriovenous malformation;
[Gastrointestinal];
GI hemorrhage (onset usually in 5th -6th decade);
Angiodysplasia;
Telangiectases (stomach, duodenum, small bowel, colon);
Arteriovenous malformation;
Melena;
Hematochezia;
Hematemesis

SKELETAL:
[Hands];
Nail bed telangiectases;
Finger pad telangiectases;
Clubbing

SKIN, NAILS, HAIR:
[Skin];
Telangiectases (especially on tongue, lips, palate, fingers, face,
conjunctiva, trunk, nail beds, and fingertips)

NEUROLOGIC:
[Central nervous system];
Cerebral arteriovenous malformation;
Migraine headache;
Transient ischemic attack;
Ischemic stroke;
Seizure;
Subarachnoid hemorrhage;
Spinal arteriovenous malformation;
Intracerebral hemorrhage;
Brain abscess;
Paradoxical cerebral emboli

HEMATOLOGY:
Polycythemia;
Anemia

MISCELLANEOUS:
Definite diagnosis if 3/4 criteria present (epistaxis, telangiectasia,
visceral lesion, or family history);
Cutaneous telangiectases often not evident until 20-30 years of age
Incidence 1 in 5,000-8,000;
Genetic heterogeneity;
PAVMs occur more frequently in hereditary hemorrhagic telangiectasia
1 (HHT1) than HHT2

MOLECULAR BASIS:
Caused by mutation in the endoglin gene (ENG, 131195.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 12/15/2006
Kelly A. Przylepa - revised: 8/22/2000

*FIELD* ED
joanna: 10/31/2013
joanna: 7/20/2012
joanna: 5/18/2011
joanna: 1/19/2007
ckniffin: 12/15/2006
joanna: 12/4/2002
joanna: 10/2/2001
joanna: 9/13/2001
kayiaros: 8/22/2000

*FIELD* CN
Ada Hamosh - updated: 1/31/2014
Ada Hamosh - updated: 6/20/2012
Marla J. F. O'Neill - updated: 7/26/2010
Cassandra L. Kniffin - updated: 5/27/2010
Marla J. F. O'Neill - updated: 10/5/2009
Cassandra L. Kniffin - updated: 7/21/2009
Cassandra L. Kniffin - updated: 9/16/2008
Victor A. McKusick - updated: 9/29/2006
Marla J. F. O'Neill - updated: 7/7/2006
Cassandra L. Kniffin - updated: 4/27/2006
Cassandra L. Kniffin - updated: 3/21/2006
Deborah L. Stone - updated: 7/23/2004
Victor A. McKusick - updated: 5/5/2004
Victor A. McKusick - updated: 12/23/2003
John A. Phillips, III - updated: 11/7/2002
Victor A. McKusick - updated: 2/21/2002
Victor A. McKusick - updated: 10/2/2001
Gary A. Bellus - updated: 4/5/2001
Victor A. McKusick - updated: 10/23/2000
Victor A. McKusick - updated: 3/23/2000
Victor A. McKusick - updated: 3/15/2000
Victor A. McKusick - updated: 8/12/1999
Ada Hamosh - updated: 6/1/1999
Victor A. McKusick - updated: 1/20/1999
Victor A. McKusick - updated: 6/12/1998
Victor A. McKusick - updated: 5/19/1998

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

*FIELD* ED
alopez: 01/31/2014
alopez: 1/31/2014
carol: 10/31/2013
carol: 9/16/2013
alopez: 6/26/2012
terry: 6/20/2012
joanna: 4/25/2012
carol: 8/29/2011
terry: 8/26/2011
terry: 1/13/2011
carol: 12/22/2010
carol: 10/4/2010
wwang: 7/30/2010
terry: 7/26/2010
wwang: 6/15/2010
ckniffin: 5/27/2010
wwang: 10/22/2009
terry: 10/5/2009
wwang: 9/4/2009
ckniffin: 7/21/2009
terry: 6/3/2009
terry: 4/8/2009
ckniffin: 3/20/2009
terry: 2/9/2009
wwang: 9/24/2008
ckniffin: 9/16/2008
wwang: 12/21/2006
ckniffin: 12/15/2006
carol: 11/10/2006
alopez: 10/13/2006
terry: 9/29/2006
wwang: 7/7/2006
wwang: 5/3/2006
ckniffin: 4/27/2006
wwang: 3/23/2006
ckniffin: 3/21/2006
terry: 2/18/2005
tkritzer: 7/26/2004
terry: 7/23/2004
carol: 6/8/2004
tkritzer: 6/1/2004
terry: 5/5/2004
carol: 4/29/2004
cwells: 12/24/2003
terry: 12/23/2003
tkritzer: 10/8/2003
tkritzer: 10/1/2003
alopez: 11/7/2002
terry: 3/5/2002
cwells: 2/25/2002
terry: 2/21/2002
carol: 10/2/2001
terry: 10/2/2001
cwells: 4/11/2001
cwells: 4/5/2001
terry: 3/26/2001
carol: 11/9/2000
mcapotos: 11/6/2000
terry: 10/23/2000
mcapotos: 3/28/2000
terry: 3/23/2000
terry: 3/15/2000
carol: 8/16/1999
alopez: 8/12/1999
terry: 8/12/1999
terry: 6/11/1999
alopez: 6/1/1999
carol: 1/28/1999
terry: 1/20/1999
carol: 6/19/1998
dholmes: 6/12/1998
carol: 5/30/1998
terry: 5/28/1998
terry: 5/19/1998
alopez: 5/8/1998
dholmes: 5/7/1998
terry: 7/10/1997
terry: 10/30/1996
jamie: 10/23/1996
jamie: 10/16/1996
mark: 9/26/1996
terry: 9/23/1996
carol: 8/22/1996
marlene: 8/2/1996
terry: 7/25/1996
mark: 2/19/1996
terry: 2/15/1996
mark: 11/1/1995
carol: 2/7/1995
jburn: 10/27/1994
terry: 7/27/1994
jason: 7/19/1994
warfield: 4/21/1994

RBCC Red Blood Cell Collection

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