RBCC Red Blood Cell Collection

AGT (SERPINA8) [Confidence: low (only semi-automatic identification from reviews)]
Angiotensinogen (Serpin A8; Angiotensin-1; Angiotensin 1-10; Angiotensin I; Ang I; Angiotensin-2; Angiotensin 1-8; Angiotensin II; Ang II; Angiotensin-3; Angiotensin 2-8; Angiotensin III; Ang III; Des-Asp[1]-angiotensin II; Angiotensin-4; Angiotensin 3-8; Angiotensin IV; Ang IV; Angiotensin 1-9; Angiotensin 1-7; Angiotensin 1-5; Angiotensin 1-4; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01019
ID ANGT_HUMAN Reviewed; 485 AA.
AC P01019; Q16358; Q16359; Q96F91;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 170.
DE RecName: Full=Angiotensinogen;
DE AltName: Full=Serpin A8;
DE Contains:
DE RecName: Full=Angiotensin-1;
DE AltName: Full=Angiotensin 1-10;
DE AltName: Full=Angiotensin I;
DE Short=Ang I;
DE Contains:
DE RecName: Full=Angiotensin-2;
DE AltName: Full=Angiotensin 1-8;
DE AltName: Full=Angiotensin II;
DE Short=Ang II;
DE Contains:
DE RecName: Full=Angiotensin-3;
DE AltName: Full=Angiotensin 2-8;
DE AltName: Full=Angiotensin III;
DE Short=Ang III;
DE AltName: Full=Des-Asp[1]-angiotensin II;
DE Contains:
DE RecName: Full=Angiotensin-4;
DE AltName: Full=Angiotensin 3-8;
DE AltName: Full=Angiotensin IV;
DE Short=Ang IV;
DE Contains:
DE RecName: Full=Angiotensin 1-9;
DE Contains:
DE RecName: Full=Angiotensin 1-7;
DE Contains:
DE RecName: Full=Angiotensin 1-5;
DE Contains:
DE RecName: Full=Angiotensin 1-4;
DE Flags: Precursor;
GN Name=AGT; Synonyms=SERPINA8;
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].
RX PubMed=6089875; DOI=10.1021/bi00311a006;
RA Kageyama R., Ohkubo H., Nakanishi S.;
RT "Primary structure of human preangiotensinogen deduced from the cloned
RT cDNA sequence.";
RL Biochemistry 23:3603-3609(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2924688;
RA Gaillard I., Clauser E., Corvol P.;
RT "Structure of human angiotensinogen gene.";
RL DNA 8:87-99(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1692023;
RA Fukamizu A., Takahashi S., Seo M.S., Tada M., Tanimoto K., Uehara S.,
RA Murakami K.;
RT "Structure and expression of the human angiotensinogen gene.
RT Identification of a unique and highly active promoter.";
RL J. Biol. Chem. 265:7576-7582(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-335.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-338.
RX PubMed=2885106;
RA Kunapuli S.P., Kumar A.;
RT "Molecular cloning of human angiotensinogen cDNA and evidence for the
RT presence of its mRNA in rat heart.";
RL Circ. Res. 60:786-790(1987).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 32-184.
RX PubMed=3579322; DOI=10.1016/0003-9861(87)90148-2;
RA Kunapuli S.P., Benedict C.R., Kumar A.;
RT "Tissue specific hormonal regulation of the rat angiotensinogen gene
RT expression.";
RL Arch. Biochem. Biophys. 254:642-646(1987).
RN [7]
RP PROTEIN SEQUENCE OF 34-58.
RX PubMed=7259779; DOI=10.1016/0006-291X(81)90762-2;
RA Tewksbury D.A., Dart R.A., Travis J.;
RT "The amino terminal amino acid sequence of human angiotensinogen.";
RL Biochem. Biophys. Res. Commun. 99:1311-1315(1981).
RN [8]
RP PROTEIN SEQUENCE OF 34-45, AND SUBUNIT.
RC TISSUE=Serum;
RX PubMed=7539791; DOI=10.1074/jbc.270.23.13645;
RA Oxvig C., Haaning J., Kristensen L., Wagner J.M., Rubin I.,
RA Stigbrand T., Gleich G.J., Sottrup-Jensen L.;
RT "Identification of angiotensinogen and complement C3dg as novel
RT proteins binding the proform of eosinophil major basic protein in
RT human pregnancy serum and plasma.";
RL J. Biol. Chem. 270:13645-13651(1995).
RN [9]
RP PROTEIN SEQUENCE OF 34-43.
RX PubMed=4300938;
RA Arakawa K., Minohara A., Yamada J., Nakamura M.;
RT "Enzymatic degradation and electrophoresis of human angiotensin I.";
RL Biochim. Biophys. Acta 168:106-112(1968).
RN [10]
RP GLYCOSYLATION AT ASN-47; ASN-170; ASN-304 AND ASN-328.
RX PubMed=3934016; DOI=10.1016/0303-7207(85)90039-5;
RA Campbell D.J., Bouhnik J., Coezy E., Menard J., Corvol P.;
RT "Processing of rat and human angiotensinogen precursors by microsomal
RT membranes.";
RL Mol. Cell. Endocrinol. 43:31-40(1985).
RN [11]
RP FUNCTION OF ANGIOTENSIN-3.
RX PubMed=1132082;
RA Goodfriend T.L., Peach M.J.;
RT "Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and
RT speculation for its role as an important agonist in the renin -
RT angiotensin system.";
RL Circ. Res. 36:38-48(1975).
RN [12]
RP FUNCTION OF ANGIOTENSIN-2.
RX PubMed=10619573; DOI=10.1016/S0895-7061(99)00103-X;
RA Weir M.R., Dzau V.J.;
RT "The renin-angiotensin-aldosterone system: a specific target for
RT hypertension management.";
RL Am. J. Hypertens. 12:205S-213S(1999).
RN [13]
RP CLEAVAGE BY ACE AND ACE2.
RX PubMed=10969042;
RA Donoghue M., Hsieh F., Baronas E., Godbout K., Gosselin M.,
RA Stagliano N., Donovan M., Woolf B., Robison K., Jeyaseelan R.,
RA Breitbart R.E., Acton S.;
RT "A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2)
RT converts angiotensin I to angiotensin 1-9.";
RL Circ. Res. 87:E1-E9(2000).
RN [14]
RP CLEAVAGE OF ANGIOTENSIN-1 AND ANGIOTENSIN-2 BY ACE2.
RX PubMed=11815627; DOI=10.1074/jbc.M200581200;
RA Vickers C., Hales P., Kaushik V., Dick L., Gavin J., Tang J.,
RA Godbout K., Parsons T., Baronas E., Hsieh F., Acton S., Patane M.A.,
RA Nichols A., Tummino P.;
RT "Hydrolysis of biological peptides by human angiotensin-converting
RT enzyme-related carboxypeptidase.";
RL J. Biol. Chem. 277:14838-14843(2002).
RN [15]
RP ANGIOTENSIN PEPTIDES METABOLISM.
RX PubMed=15283675; DOI=10.1042/BJ20040634;
RA Rice G.I., Thomas D.A., Grant P.J., Turner A.J., Hooper N.M.;
RT "Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2
RT and neprilysin in angiotensin peptide metabolism.";
RL Biochem. J. 383:45-51(2004).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-47, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [17]
RP DECARBOXYLATION AT ASP-34, FUNCTION, AND MASS SPECTROMETRY.
RX PubMed=17138938; DOI=10.1161/01.ATV.0000253889.09765.5f;
RA Jankowski V., Vanholder R., van der Giet M., Tolle M., Karadogan S.,
RA Gobom J., Furkert J., Oksche A., Krause E., Tran T.N., Tepel M.,
RA Schuchardt M., Schluter H., Wiedon A., Beyermann M., Bader M.,
RA Todiras M., Zidek W., Jankowski J.;
RT "Mass-spectrometric identification of a novel angiotensin peptide in
RT human plasma.";
RL Arterioscler. Thromb. Vasc. Biol. 27:297-302(2007).
RN [18]
RP REVIEW ON THE RENIN-ANGIOTENSIN SYSTEM.
RX PubMed=18793332; DOI=10.1111/j.1365-2796.2008.01981.x;
RA Fyhrquist F., Saijonmaa O.;
RT "Renin-angiotensin system revisited.";
RL J. Intern. Med. 264:224-236(2008).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-47, AND MASS 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 [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP STRUCTURE BY NMR OF ANGIOTENSIN-2.
RX PubMed=9492317; DOI=10.1046/j.1432-1327.1998.2510448.x;
RA Carpenter K.A., Wilkes B.C., Schiller P.W.;
RT "The octapeptide angiotensin II adopts a well-defined structure in a
RT phospholipid environment.";
RL Eur. J. Biochem. 251:448-453(1998).
RN [22]
RP STRUCTURE BY NMR OF 34-43, AND STRUCTURE BY NMR OF 34-41.
RX PubMed=12752436; DOI=10.1046/j.1432-1033.2003.03573.x;
RA Spyroulias G.A., Nikolakopoulou P., Tzakos A., Gerothanassis I.P.,
RA Magafa V., Manessi-Zoupa E., Cordopatis P.;
RT "Comparison of the solution structures of angiotensin I & II.
RT Implication for structure-function relationship.";
RL Eur. J. Biochem. 270:2163-2173(2003).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (4.33 ANGSTROMS) OF 34-485 IN COMPLEX WITH
RP RENIN, AND DISULFIDE BOND.
RX PubMed=20927107; DOI=10.1038/nature09505;
RA Zhou A., Carrell R.W., Murphy M.P., Wei Z., Yan Y., Stanley P.L.,
RA Stein P.E., Broughton Pipkin F., Read R.J.;
RT "A redox switch in angiotensinogen modulates angiotensin release.";
RL Nature 468:108-111(2010).
RN [24]
RP VARIANTS MET-207; THR-268 AND CYS-281.
RX PubMed=1394429; DOI=10.1016/0092-8674(92)90275-H;
RA Jeunemaitre X., Soubrier F., Kotelevtsev Y.V., Lifton R.P.,
RA Williams C.S., Charru A., Hunt S.C., Hopkins P.N., Williams R.R.,
RA Lalouel J.-M., Corvol P.;
RT "Molecular basis of human hypertension: role of angiotensinogen.";
RL Cell 71:169-180(1992).
RN [25]
RP VARIANT THR-268.
RX PubMed=8513325; DOI=10.1038/ng0593-59;
RA Ward K., Hata A., Jeunemaitre X., Helin C., Nelson L., Namikawa C.,
RA Farrington P.F., Ogasawara M., Suzumori K., Tomoda S., Berrebi S.,
RA Sasaki M., Corvol P., Lifton R.P., Lalouel J.-M.;
RT "A molecular variant of angiotensinogen associated with
RT preeclampsia.";
RL Nat. Genet. 4:59-61(1993).
RN [26]
RP VARIANTS ILE-242; ARG-244 AND CYS-281.
RX PubMed=7607642; DOI=10.1007/BF00214197;
RA Hixson J.E., Powers P.K.;
RT "Detection and characterization of new mutations in the human
RT angiotensinogen gene (AGT).";
RL Hum. Genet. 96:110-112(1995).
RN [27]
RP VARIANT PHE-43.
RX PubMed=7744780; DOI=10.1074/jbc.270.19.11430;
RA Inoue I., Rohrwasser A., Helin C., Jeunemaitre X., Crain P.,
RA Bohlender J., Lifton R.P., Corvol P., Ward K., Lalouel J.-M.;
RT "A mutation of angiotensinogen in a patient with preeclampsia leads to
RT altered kinetics of the renin-angiotensin system.";
RL J. Biol. Chem. 270:11430-11436(1995).
RN [28]
RP CHARACTERIZATION OF VARIANT CYS-281.
RX PubMed=8621667; DOI=10.1074/jbc.271.16.9838;
RA Gimenez-Roqueplo A.P., Leconte I., Cohen P., Simon D., Guyene T.T.,
RA Celerier J., Pau B., Corvol P., Clauser E., Jeunemaitre X.;
RT "The natural mutation Y248C of human angiotensinogen leads to abnormal
RT glycosylation and altered immunological recognition of the protein.";
RL J. Biol. Chem. 271:9838-9844(1996).
RN [29]
RP VARIANT RTD GLN-375.
RX PubMed=16116425; DOI=10.1038/ng1623;
RA Gribouval O., Gonzales M., Neuhaus T., Aziza J., Bieth E., Laurent N.,
RA Bouton J.M., Feuillet F., Makni S., Ben Amar H., Laube G.,
RA Delezoide A.-L., Bouvier R., Dijoud F., Ollagnon-Roman E., Roume J.,
RA Joubert M., Antignac C., Gubler M.-C.;
RT "Mutations in genes in the renin-angiotensin system are associated
RT with autosomal recessive renal tubular dysgenesis.";
RL Nat. Genet. 37:964-968(2005).
CC -!- FUNCTION: Essential component of the renin-angiotensin system
CC (RAS), a potent regulator of blood pressure, body fluid and
CC electrolyte homeostasis.
CC -!- FUNCTION: Angiotensin-2: acts directly on vascular smooth muscle
CC as a potent vasoconstrictor, affects cardiac contractility and
CC heart rate through its action on the sympathetic nervous system,
CC and alters renal sodium and water absorption through its ability
CC to stimulate the zona glomerulosa cells of the adrenal cortex to
CC synthesize and secrete aldosterone.
CC -!- FUNCTION: Angiotensin-3: stimulates aldosterone release.
CC -!- FUNCTION: Angiotensin 1-7: is a ligand for the G-protein coupled
CC receptor MAS1 (By similarity). Has vasodilator and antidiuretic
CC effects (By similarity). Has an antithrombotic effect that
CC involves MAS1-mediated release of nitric oxide from platelets (By
CC similarity).
CC -!- SUBUNIT: During pregnancy, exists as a disulfide-linked 2:2
CC heterotetramer with the proform of PRG2 and as a complex (probably
CC a 2:2:2 heterohexamer) with pro-PRG2 and C3dg.
CC -!- INTERACTION:
CC P30556:AGTR1; NbExp=2; IntAct=EBI-6622938, EBI-6623016;
CC P25095:Agtr1 (xeno); NbExp=10; IntAct=EBI-751728, EBI-764979;
CC P50052:AGTR2; NbExp=2; IntAct=EBI-2927577, EBI-1748067;
CC Q10714:Ance (xeno); NbExp=2; IntAct=EBI-751728, EBI-115736;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- PTM: Beta-decarboxylation of Asp-34 in angiotensin-2, by
CC mononuclear leukocytes produces alanine. The resulting peptide
CC form, angiotensin-A, has the same affinity for the AT1 receptor as
CC angiotensin-2, but a higher affinity for the AT2 receptor.
CC -!- PTM: In response to low blood pressure, the enzyme renin/REN
CC cleaves angiotensinogen to produce angiotensin-1. Angiotensin-1 is
CC a substrate of ACE (angiotensin converting enzyme) that removes a
CC dipeptide to yield the physiologically active peptide angiotensin-
CC 2. Angiotensin-1 and angiotensin-2 can be further processed to
CC generate angiotensin-3, angiotensin-4. Angiotensin 1-9 is cleaved
CC from angiotensin-1 by ACE2 and can be further processed by ACE to
CC produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4.
CC Angiotensin 1-7 has also been proposed to be cleaved from
CC angiotensin-2 by ACE2 or from angiotensin-1 by MME (neprilysin).
CC -!- PTM: The disulfide bond is labile. Angiotensinogen is present in
CC the circulation in a near 40:60 ratio with the oxidized disulfide-
CC bonded form, which preferentially interacts with receptor-bound
CC renin.
CC -!- DISEASE: Essential hypertension (EHT) [MIM:145500]: A condition in
CC which blood pressure is consistently higher than normal with no
CC identifiable cause. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry.
CC -!- DISEASE: Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal
CC recessive severe disorder of renal tubular development
CC characterized by persistent fetal anuria and perinatal death,
CC probably due to pulmonary hypoplasia from early-onset
CC oligohydramnios (the Potter phenotype). Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the serpin family.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-10 is the initiator.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/AGT";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=AGT";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Angiotensin entry;
CC URL="http://en.wikipedia.org/wiki/Angiotensin";
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DR EMBL; K02215; AAA51731.1; -; mRNA.
DR EMBL; M24689; AAA51679.1; -; Genomic_DNA.
DR EMBL; M24686; AAA51679.1; JOINED; Genomic_DNA.
DR EMBL; M24687; AAA51679.1; JOINED; Genomic_DNA.
DR EMBL; M24688; AAA51679.1; JOINED; Genomic_DNA.
DR EMBL; X15324; CAA33385.1; -; Genomic_DNA.
DR EMBL; X15325; CAA33385.1; JOINED; Genomic_DNA.
DR EMBL; X15326; CAA33385.1; JOINED; Genomic_DNA.
DR EMBL; X15327; CAA33385.1; JOINED; Genomic_DNA.
DR EMBL; BC011519; AAH11519.1; -; mRNA.
DR EMBL; M69110; AAA52282.1; -; mRNA.
DR EMBL; S78529; AAD14287.1; -; Genomic_DNA.
DR EMBL; S78530; AAD14288.1; -; Genomic_DNA.
DR PIR; A35203; ANHU.
DR RefSeq; NP_000020.1; NM_000029.3.
DR UniGene; Hs.19383; -.
DR PDB; 1N9U; NMR; -; A=34-43.
DR PDB; 1N9V; NMR; -; A=34-41.
DR PDB; 2JP8; NMR; -; P=34-40.
DR PDB; 2WXW; X-ray; 3.30 A; A=34-485.
DR PDB; 2X0B; X-ray; 4.33 A; B/D/F/H=34-485.
DR PDB; 4AA1; X-ray; 1.99 A; P=34-41.
DR PDB; 4APH; X-ray; 1.99 A; P=34-41.
DR PDB; 4FYS; X-ray; 2.01 A; C=36-41.
DR PDBsum; 1N9U; -.
DR PDBsum; 1N9V; -.
DR PDBsum; 2JP8; -.
DR PDBsum; 2WXW; -.
DR PDBsum; 2X0B; -.
DR PDBsum; 4AA1; -.
DR PDBsum; 4APH; -.
DR PDBsum; 4FYS; -.
DR ProteinModelPortal; P01019; -.
DR SMR; P01019; 34-482.
DR DIP; DIP-309N; -.
DR IntAct; P01019; 8.
DR MINT; MINT-1472115; -.
DR STRING; 9606.ENSP00000355627; -.
DR DrugBank; DB01258; Aliskiren.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB01340; Cilazapril.
DR DrugBank; DB01029; Irbesartan.
DR DrugBank; DB00722; Lisinopril.
DR DrugBank; DB01092; Ouabain.
DR DrugBank; DB00641; Simvastatin.
DR MEROPS; I04.953; -.
DR PhosphoSite; P01019; -.
DR DMDM; 113880; -.
DR SWISS-2DPAGE; P01019; -.
DR PaxDb; P01019; -.
DR PeptideAtlas; P01019; -.
DR PRIDE; P01019; -.
DR DNASU; 183; -.
DR Ensembl; ENST00000366667; ENSP00000355627; ENSG00000135744.
DR GeneID; 183; -.
DR KEGG; hsa:183; -.
DR UCSC; uc001hty.4; human.
DR CTD; 183; -.
DR GeneCards; GC01M230838; -.
DR HGNC; HGNC:333; AGT.
DR HPA; HPA001557; -.
DR MIM; 106150; gene.
DR MIM; 145500; phenotype.
DR MIM; 267430; phenotype.
DR neXtProt; NX_P01019; -.
DR Orphanet; 243761; Essential hypertension.
DR Orphanet; 97369; Renal tubular dysgenesis of genetic origin.
DR PharmGKB; PA42; -.
DR eggNOG; NOG314543; -.
DR HOVERGEN; HBG004233; -.
DR InParanoid; P01019; -.
DR KO; K09821; -.
DR OMA; RFMQAVT; -.
DR OrthoDB; EOG7QK0BN; -.
DR PhylomeDB; P01019; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_17015; Metabolism of proteins.
DR ChiTaRS; AGT; human.
DR EvolutionaryTrace; P01019; -.
DR GeneWiki; Angiotensin; -.
DR GenomeRNAi; 183; -.
DR NextBio; 748; -.
DR PMAP-CutDB; P01019; -.
DR PRO; PR:P01019; -.
DR ArrayExpress; P01019; -.
DR Bgee; P01019; -.
DR CleanEx; HS_AGT; -.
DR Genevestigator; P01019; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0010698; F:acetyltransferase activator activity; IDA:BHF-UCL.
DR GO; GO:0008083; F:growth factor activity; TAS:BHF-UCL.
DR GO; GO:0005179; F:hormone activity; ISS:BHF-UCL.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:RefGenome.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Ensembl.
DR GO; GO:0007202; P:activation of phospholipase C activity; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0002003; P:angiotensin maturation; TAS:Reactome.
DR GO; GO:0001998; P:angiotensin mediated vasoconstriction involved in regulation of systemic arterial blood pressure; IEA:Ensembl.
DR GO; GO:0003051; P:angiotensin-mediated drinking behavior; IEA:Ensembl.
DR GO; GO:0014824; P:artery smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0048143; P:astrocyte activation; IEA:Ensembl.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0001974; P:blood vessel remodeling; TAS:BHF-UCL.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IEA:Ensembl.
DR GO; GO:0035411; P:catenin import into nucleus; IEA:Ensembl.
DR GO; GO:0061049; P:cell growth involved in cardiac muscle cell development; IEA:Ensembl.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0007160; P:cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; IEA:Ensembl.
DR GO; GO:0050663; P:cytokine secretion; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0008065; P:establishment of blood-nerve barrier; IEA:Ensembl.
DR GO; GO:0007588; P:excretion; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl.
DR GO; GO:0048144; P:fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0007199; P:G-protein coupled receptor signaling pathway coupled to cGMP nucleotide second messenger; TAS:BHF-UCL.
DR GO; GO:0001822; P:kidney development; IMP:BHF-UCL.
DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; NAS:BHF-UCL.
DR GO; GO:0030308; P:negative regulation of cell growth; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0051387; P:negative regulation of neurotrophin TRK receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0034104; P:negative regulation of tissue remodeling; IEA:Ensembl.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; TAS:BHF-UCL.
DR GO; GO:0001543; P:ovarian follicle rupture; IEA:Ensembl.
DR GO; GO:0030432; P:peristalsis; IEA:Ensembl.
DR GO; GO:0007200; P:phospholipase C-activating G-protein coupled receptor signaling pathway; NAS:BHF-UCL.
DR GO; GO:0010535; P:positive regulation of activation of JAK2 kinase activity; IMP:UniProtKB.
DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IDA:UniProtKB.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:BHF-UCL.
DR GO; GO:0010873; P:positive regulation of cholesterol esterification; IDA:BHF-UCL.
DR GO; GO:0001819; P:positive regulation of cytokine production; TAS:BHF-UCL.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0003331; P:positive regulation of extracellular matrix constituent secretion; IEA:Ensembl.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0045723; P:positive regulation of fatty acid biosynthetic process; IEA:Ensembl.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; ISS:BHF-UCL.
DR GO; GO:0050729; P:positive regulation of inflammatory response; TAS:BHF-UCL.
DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; IC:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IEA:Ensembl.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0033864; P:positive regulation of NAD(P)H oxidase activity; TAS:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:BHF-UCL.
DR GO; GO:0046622; P:positive regulation of organ growth; IEA:Ensembl.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IDA:BHF-UCL.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IMP:UniProtKB.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; TAS:BHF-UCL.
DR GO; GO:0035815; P:positive regulation of renal sodium excretion; IEA:Ensembl.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IEA:Ensembl.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0002034; P:regulation of blood vessel size by renin-angiotensin; TAS:BHF-UCL.
DR GO; GO:0051924; P:regulation of calcium ion transport; IEA:Ensembl.
DR GO; GO:0001558; P:regulation of cell growth; NAS:BHF-UCL.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0014061; P:regulation of norepinephrine secretion; IEA:Ensembl.
DR GO; GO:0030162; P:regulation of proteolysis; IBA:RefGenome.
DR GO; GO:0002019; P:regulation of renal output by angiotensin; NAS:BHF-UCL.
DR GO; GO:0035813; P:regulation of renal sodium excretion; NAS:BHF-UCL.
DR GO; GO:0019229; P:regulation of vasoconstriction; NAS:BHF-UCL.
DR GO; GO:0001999; P:renal response to blood flow involved in circulatory renin-angiotensin regulation of systemic arterial blood pressure; IEA:Ensembl.
DR GO; GO:0002018; P:renin-angiotensin regulation of aldosterone production; NAS:BHF-UCL.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0014873; P:response to muscle activity involved in regulation of muscle adaptation; ISS:BHF-UCL.
DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0051145; P:smooth muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0048659; P:smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; IEA:Ensembl.
DR GO; GO:0042311; P:vasodilation; IEA:Ensembl.
DR InterPro; IPR000227; Angiotensinogen.
DR InterPro; IPR023795; Serpin_CS.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR Pfam; PF00079; Serpin; 1.
DR PRINTS; PR00654; ANGIOTENSNGN.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
DR PROSITE; PS00284; SERPIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Polymorphism;
KW Reference proteome; Secreted; Signal; Vasoactive; Vasoconstrictor.
FT SIGNAL 1 33
FT CHAIN 34 485 Angiotensinogen.
FT /FTId=PRO_0000032456.
FT PEPTIDE 34 43 Angiotensin-1.
FT /FTId=PRO_0000032457.
FT PEPTIDE 34 42 Angiotensin 1-9.
FT /FTId=PRO_0000420659.
FT PEPTIDE 34 41 Angiotensin-2.
FT /FTId=PRO_0000032458.
FT PEPTIDE 34 40 Angiotensin 1-7.
FT /FTId=PRO_0000420660.
FT PEPTIDE 34 38 Angiotensin 1-5.
FT /FTId=PRO_0000420661.
FT PEPTIDE 34 37 Angiotensin 1-4.
FT /FTId=PRO_0000420662.
FT PEPTIDE 35 41 Angiotensin-3.
FT /FTId=PRO_0000032459.
FT PEPTIDE 36 41 Angiotensin-4.
FT /FTId=PRO_0000420663.
FT MOD_RES 34 34 Beta-decarboxylated aspartate; in form
FT angiotensin-A.
FT CARBOHYD 47 47 N-linked (GlcNAc...).
FT CARBOHYD 170 170 N-linked (GlcNAc...).
FT CARBOHYD 304 304 N-linked (GlcNAc...).
FT CARBOHYD 328 328 N-linked (GlcNAc...).
FT DISULFID 51 171
FT VARIANT 43 43 L -> F (associated with susceptibility to
FT pre-eclampsia; alters the reactions with
FT renin and angiotensin-converting enzyme;
FT dbSNP:rs41271499).
FT /FTId=VAR_022933.
FT VARIANT 98 98 E -> K (in dbSNP:rs11568032).
FT /FTId=VAR_029166.
FT VARIANT 114 114 G -> C (in dbSNP:rs2229389).
FT /FTId=VAR_051939.
FT VARIANT 137 137 T -> M (in dbSNP:rs34829218).
FT /FTId=VAR_035431.
FT VARIANT 207 207 T -> M (associated with hypertension;
FT dbSNP:rs4762).
FT /FTId=VAR_007093.
FT VARIANT 242 242 T -> I (associated with susceptibility to
FT hypertension).
FT /FTId=VAR_007094.
FT VARIANT 244 244 L -> R (associated with susceptibility to
FT hypertension; dbSNP:rs5041).
FT /FTId=VAR_007095.
FT VARIANT 268 268 M -> I (in dbSNP:rs11568053).
FT /FTId=VAR_029167.
FT VARIANT 268 268 M -> T (associated with essential
FT hypertension and pre-eclampsia;
FT dbSNP:rs699).
FT /FTId=VAR_007096.
FT VARIANT 281 281 Y -> C (associated with susceptibility to
FT hypertension; alters the structure,
FT glycosylation and secretion of
FT angiotensinogen; dbSNP:rs56073403).
FT /FTId=VAR_007097.
FT VARIANT 335 335 P -> S (in dbSNP:rs17856352).
FT /FTId=VAR_035432.
FT VARIANT 375 375 R -> Q (in RTD).
FT /FTId=VAR_035433.
FT VARIANT 392 392 L -> M (in dbSNP:rs1805090).
FT /FTId=VAR_014573.
FT CONFLICT 51 51 C -> S (in Ref. 7; AA sequence).
FT CONFLICT 58 58 N -> D (in Ref. 7; AA sequence).
FT CONFLICT 333 333 Q -> E (in Ref. 2; AAA51679).
FT TURN 42 44
FT HELIX 48 57
FT STRAND 59 62
FT HELIX 81 93
FT HELIX 97 117
FT HELIX 118 120
FT TURN 124 126
FT STRAND 129 134
FT HELIX 136 148
FT HELIX 154 162
FT TURN 171 173
FT HELIX 177 191
FT TURN 195 197
FT STRAND 203 212
FT HELIX 221 230
FT STRAND 234 236
FT HELIX 244 259
FT STRAND 277 288
FT STRAND 291 293
FT STRAND 302 305
FT STRAND 313 322
FT TURN 325 328
FT STRAND 329 333
FT TURN 337 339
FT STRAND 340 349
FT HELIX 353 358
FT HELIX 365 368
FT STRAND 374 381
FT STRAND 385 391
FT HELIX 392 395
FT HELIX 402 406
FT STRAND 407 409
FT STRAND 425 434
FT STRAND 452 455
FT STRAND 460 466
FT TURN 467 470
FT STRAND 475 479
SQ SEQUENCE 485 AA; 53154 MW; 5026C2DFB2DD236E CRC64;
MRKRAPQSEM APAGVSLRAT ILCLLAWAGL AAGDRVYIHP FHLVIHNEST CEQLAKANAG
KPKDPTFIPA PIQAKTSPVD EKALQDQLVL VAAKLDTEDK LRAAMVGMLA NFLGFRIYGM
HSELWGVVHG ATVLSPTAVF GTLASLYLGA LDHTADRLQA ILGVPWKDKN CTSRLDAHKV
LSALQAVQGL LVAQGRADSQ AQLLLSTVVG VFTAPGLHLK QPFVQGLALY TPVVLPRSLD
FTELDVAAEK IDRFMQAVTG WKTGCSLMGA SVDSTLAFNT YVHFQGKMKG FSLLAEPQEF
WVDNSTSVSV PMLSGMGTFQ HWSDIQDNFS VTQVPFTESA CLLLIQPHYA SDLDKVEGLT
FQQNSLNWMK KLSPRTIHLT MPQLVLQGSY DLQDLLAQAE LPAILHTELN LQKLSNDRIR
VGEVLNSIFF ELEADEREPT ESTQQLNKPE VLEVTLNRPF LFAVYDQSAT ALHFLGRVAN
PLSTA
//

MIM 106150
*RECORD*
*FIELD* NO
106150
*FIELD* TI
+106150 ANGIOTENSINOGEN; AGT
;;SERPINA8
IgA NEPHROPATHY, PROGRESSION TO RENAL FAILURE IN, SUSCEPTIBILITY TO,
read moreINCLUDED;;
ANGIOTENSIN I, INCLUDED;;
ANGIOTENSIN II, INCLUDED
*FIELD* TX

DESCRIPTION

Angiotensin is formed from a precursor, angiotensinogen, which is
produced by the liver and found in the alpha-globulin fraction of
plasma. The lowering of blood pressure is a stimulus to secretion of
renin (179820) by the kidney into the blood. Renin cleaves from
angiotensinogen a terminal decapeptide, angiotensin I. This is further
altered by the enzymatic removal of a dipeptide to form angiotensin II.

CLONING

Ohkubo et al. (1983) determined the sequence of the cloned rat
angiotensinogen gene. The human angiotensinogen molecule has a molecular
mass of about 50 kD. The angiotensin I decapeptide is located in its
N-terminal part. Kageyama et al. (1984) reported the complete nucleotide
sequence of human angiotensinogen mRNA. Similarly, Kunapuli et al.
(1987) isolated cDNA clones for human angiotensinogen from a human liver
library. The determined nucleotide sequence corroborated the sequence
published by Kageyama et al. (1984), with the exception of a single
nucleotide change which may represent a simple genetic polymorphism.
Kunapuli et al. (1987) constructed a full-length angiotensinogen cDNA
which enabled the in vitro synthesis of human angiotensinogen in E.
coli. Gaillard et al. (1989) observed that the primary amino acid
sequence shows similarities to that of alpha-1-antitrypsin (AAT; 107400)
and antithrombin III (AT3; 107300).

GENE STRUCTURE

Gaillard et al. (1989) found that the human angiotensinogen gene
contains 5 exons. The angiotensinogen gene shows organization identical
to that of the AAT gene, but different from that of the AT3 gene.

MAPPING

By in situ hybridization, Gaillard-Sanchez et al. (1990) assigned the
angiotensinogen gene to 1q4 in the same region as the renin gene. Isa et
al. (1989, 1990) used a human angiotensinogen cDNA plasmid probe to
localize the gene by nonisotopic in situ hybridization; the location was
determined to be 1q42-q43. By screening a panel of human-mouse somatic
cell hybrids, Abonia et al. (1993) confirmed the assignment of the AGT
locus to chromosome 1. They showed, furthermore, that the homologous
gene in the mouse is on the distal end of chromosome 8; a short region
of conserved linkage homology between mouse chromosome 8 and human
chromosome 1 was indicated by the mapping also of the skeletal
alpha-actin locus (102610) to mouse chromosome 8 and human chromosome 1.

GENE FUNCTION

Karlsson et al. (1998) analyzed the expression of angiotensinogen and
enzymes required for its conversion to angiotensin II in human adipose
tissue. Northern blot analysis demonstrated angiotensinogen expression
in adipose tissue from 9 obese subjects. Western blot analysis showed a
distinct band of expected size of the angiotensinogen protein (61 kD) in
isolated adipocytes. RT-PCR and Southern blot analysis demonstrated
renin expression in human adipose tissue. Angiotensin-converting enzyme
mRNA was detected by RT-PCR, and the identity of the PCR products was
verified by restriction enzyme cleavage. Transcripts for cathepsin D
(116840) and cathepsin G (116830), components of the
nonrenin-angiotensin systems, were detected by RT-PCR and verified by
restriction enzyme cleavage. The authors concluded that human adipose
tissue expresses angiotensinogen and enzymes of renin- and
nonrenin-angiotensin systems.

Hypertrophy is a fundamental adaptive process occurring in postmitotic
cardiac and skeletal muscle in response to mechanical load. Using an in
vitro model of load-induced cardiac hypertrophy, Sadoshima et al. (1993)
demonstrated that mechanical stress causes release of angiotensin II
from cardiac myocytes and that angiotensin II acts as an initial
mediator of the hypertrophic response. The results not only provided
direct evidence for the autocrine mechanism in load-induced growth of
cardiac muscle cells, but also defined a pathophysiologic role of the
local (cardiac) renin-angiotensin system.

To analyze the influence of the M235T polymorphism (106150.0001) on the
ethinylestradiol-induced increase in plasma AGT concentration and on the
resulting generation of Ang I and Ang II in plasma, Azizi et al. (2000)
compared changes in the circulating renin-angiotensin system after
short-term (2 days) and repeated (7 days) administration of 50 microg
ethinylestradiol in homozygous normotensive men (TT and MM). In the
7-day study, TT subjects had higher peak plasma AGT concentrations than
did MM subjects. The more pronounced AGT increase in TT subjects
resulted in similar plasma renin activity at a lower plasma active renin
concentration, with a higher plasma renin activity/active renin ratio.
The authors concluded that the T235 AGT allele is associated with
increased AGT secretion in plasma after ethinylestradiol administration.
In the short term, complete readjustment of the circulating
renin-angiotensin system occurs, through a decrease in renin release,
which blunts the effects of the increase in AGT concentration.

Aldosterone enhances angiotensin II-induced PAI1 (173360) expression in
vitro. Sawathiparnich et al. (2003) tested the hypothesis that
angiotensin II type 1 and aldosterone receptor (600983) antagonism
interact to decrease PAI1 in humans. Effects of candesartan,
spironolactone, or combined candesartan/spironolactone on mean arterial
pressure, endocrine, and fibrinolytic variables were measured in 18
normotensive subjects in whom the renin-angiotensin-aldosterone system
was activated by furosemide. This study evidenced an interactive effect
of endogenous angiotensin II and aldosterone on PAI1 production in
humans.

Albumin (ALB; 103600) endocytosis in renal proximal tubule cells through
a clathrin- and receptor-mediated mechanism initiates or promotes
tubule-interstitial disease in several pathophysiologic conditions.
Using LLC-PK1 porcine proximal tubule cells, Caruso-Neves et al. (2005)
showed that Ang II increased albumin endocytosis through Agtr2
(300034)-mediated activation of protein kinase B (AKT1; 164730) in the
plasma membrane, which depended on the basal activity of
phosphatidylinositol 3-kinase (PI3K; see 601232).

Montiel et al. (2005) found that ANG II enhanced FAK (PTK2; 600758) and
paxillin (PXN; 602505) phosphorylation in human umbilical endothelial
cells (HUVECs). ANG II induced a time- and dose-dependent augmentation
of cell migration, but it did not affect HUVEC proliferation. Inhibitor
studies indicated that FAK and paxillin phosphorylation induced HUVEC
migration through signaling pathways dependent on PI3K and SRC family
kinases (see 190090) and EGFR phosphorylation.

MOLECULAR GENETICS

Brand et al. (2002) measured plasma AGT levels and analyzed 7 biallelic
AGT variants as candidate functional variants in 545 healthy French
volunteers in 130 nuclear families that included 285 offspring. Analysis
with the class D regressive model showed the most significant result at
-532C-T (p = 0.000001), accounting for 4.3% of total plasma AGT
variability in parents and 5.5% in offspring. Maximum likelihood
estimates of haplotype frequencies and tests of linkage disequilibrium
between each AGT polymorphism and a putative QTL were in agreement with
a complete confounding of -532C-T with the QTL, when taking into account
sex- and generation-specific effects of the QTL. However, further
combined segregation-linkage analyses showed significant evidence for
additional effects of the -6G-A, M235T (106150.0001), and 2054C-A
polymorphisms after accounting for -532C-T, which supports a complex
model with at least 2 functional variants within the AGT gene
controlling AGT levels.

- Renal Tubular Dysgenesis

Gribouval et al. (2005) studied 11 individuals with renal tubular
dysgenesis (RTD; 267430) belonging to 9 families and found that they had
homozygous or compound heterozygous mutations in the genes encoding
angiotensinogen (see 106150.0003-106150.0005), renin (REN; 179820),
angiotensin-converting enzyme (ACE; 106180), or angiotensin II receptor
type 1 (AGTR1; 106165). They proposed that renal lesions and early
anuria result from chronic low perfusion pressure of the fetal kidney, a
consequence of renin-angiotensin system inactivity. This appeared to be
the first identification of a renal mendelian disorder linked to genetic
defects in the renin-angiotensin system, highlighting the crucial role
of the renin-angiotensin system in human kidney development.

- Association with Hypertension

Jeunemaitre et al. (1992) reported results from a collaborative study of
AGT in 215 sibships, each with 2 or more hypertensive subjects
ascertained from American and French study populations, a total of 379
sib pairs. The study provided evidence for involvement of AGT in the
pathogenesis of essential hypertension (145500). In each of the samples,
they found genetic linkage between essential hypertension and AGT in
affected sibs, association between hypertension and certain molecular
variants of AGT as revealed by a comparison between cases and controls,
and increased concentrations of plasma angiotensinogen in hypertensive
subjects who carry a common variant of AGT strongly associated with
hypertension. Among the 15 molecular variants of AGT that had been
identified, significant association with hypertension was observed with
2 amino acid substitutions, M235T (106150.0001) and T174M. These 2
variants exhibited complete linkage disequilibrium, as T174M occurred on
a subset of the haplotypes carrying the M235T variant, and both
haplotypes were observed at higher frequency among hypertensives.
Several interpretations can be proposed to account for this observation:
M235T directly mediates a predisposition to hypertension; an
unidentified risk factor is common to both haplotypes; or each haplotype
harbors a distinct risk factor.

Caulfield et al. (1994) could find no association between essential
hypertension and either the M235T or the T174M variant. On the other
hand, studies in a distinct, ethnically homogeneous population, namely
Japanese, showed that the same variant, T235, is associated with
essential hypertension (Hata et al., 1994). In the Japanese study, the
population frequency of the T235 variant was found to be higher than
among Caucasian subjects. Because of the involvement of angiotensinogen
in salt homeostasis, T235 may be a marker for a salt-sensitive form of
essential hypertension. Epidemiologic studies documented a striking
gradient of increasing prevalence of hypertension and stroke mortality
from south to north Japan (Takahashi et al., 1957), which correlates
with a parallel rise in average daily salt intake (Sasaki, 1964).

The observation that plasma and angiotensinogen levels correlate with
blood pressure and track through families suggested that angiotensinogen
may have a role in essential hypertension. Caulfield et al. (1994)
therefore investigated linkage between the AGT gene and essential
hypertension in 63 white European families in which 2 or more members
had essential hypertension. To test for linkage they used a dinucleotide
repeat marker flanking the gene on 1q42-q43 and adopted the
affected-pedigree-member method of linkage analysis (Weeks and Lange,
1988). In this approach, a t-statistic is computed that tests whether
affected relatives share alleles at the AGT locus more often than would
be expected by chance. Linkage was detected (t = 5.00, P less than
0.001).

Among the Hutterites, a North American religious genetic isolate
(Hostetler, 1974), Hegele et al. (1994) tested for association between
variation in systolic and diastolic blood pressures and the
insertion/deletion polymorphism of ACE (106180) and 2 protein
polymorphisms of AGT, namely, M235T and T174M. The genotypes of AGT
codon 174 were significantly associated with variation in systolic blood
pressure in men and accounted for 3.1% of the total variation. Hegele et
al. (1996) provided further information on this association and that of
the genotype of apoB codon 4154 (107730) in association with variation
in systolic blood pressure in Hutterites.

In a study in African Caribbeans from St. Vincent and the Grenadines,
Caulfield et al. (1995) tested for linkage between the AGT gene and
hypertension by analyzing 63 affected sib pairs for an excess of allele
sharing, using an AGT dinucleotide repeat sequence as an indicator.
There was significant support for linkage (P = 0.001) and association (P
less than 0.001) of AGT to hypertension. However, they found no
association of the M235T variant (106150.0001) with hypertension in this
study of African Caribbeans.

As outlined earlier, the strongest evidence implicating a gene as the
cause of human essential hypertension is for the AGT gene (Jeunemaitre
et al., 1992). Davisson et al. (1997) reported studies designed to
determine whether elements of the human renin-angiotensin system could
functionally replace elements of the mouse renin-angiotensin system by
complementing the reduced survival and renal abnormalities observed in
mice carrying a gene-targeted deletion of the mouse angiotensinogen
gene. These studies established that the human renin and angiotensinogen
genes can functionally replace the mouse angiotensinogen gene, and
provided proof that, in principle, one can examine the regulation of
elements of the human renin-angiotensin system, and test the
significance of human renin-angiotensin system gene variants, by a
combined transgenic and gene-targeting approach.

Because of previous demonstrations of association between
angiotensinogen and essential hypertension in white Europeans,
African-Caribbeans, and Japanese, Niu et al. (1998) investigated whether
the ATG gene is similarly implicated in the pathogenesis of essential
hypertension in Chinese by carrying out linkage analysis in 310
hypertensive sib pairs. Genotypes were determined for 2 diallelic DNA
polymorphisms observed at amino acid residues 174 (thr174 to met; T174M)
and 235 (met235 to thr; M235T; 106150.0001) within the coding sequence
and for 2 highly informative dinucleotide (GT)-repeat sequences (1 in
the 3-prime flanking region and 1 at a distance of 6.1 cM from the
gene). Affected sib-pair analysis conducted according to 3 different
algorithms revealed no evidence for linkage of the AGT gene to
hypertension. Niu et al. (1998) suggested that ethnicity may make a
significant difference in the role of various genes in certain complex
traits.

Nakajima et al. (2002) determined the complete genomic sequence of AGT
and performed a scan of 14.4 kb for sequence variation in AGT. They
found 44 single-nucleotide polymorphisms (SNPs) and a microsatellite in
whites and Japanese. To infer the ancestral state of each SNP, the
chimpanzee sequence was also completed. They evaluated haplotypes and
the pattern of linkage disequilibrium (LD) in AGT to provide empirical
information on the utility of LD for detection of disease genes. Despite
an overall similarity in LD patterns in the 2 populations, they found a
much higher frequency of the M235-associated haplotype in the white
population.

Wang et al. (1999) evaluated AGT as a candidate gene for hypertension by
means of sib pair analysis with multiple microsatellite markers
surrounding this locus. They also performed an association study of the
AGT variants in unrelated subjects with a strong family history (2
affected parents). For the linkage study, single and multiplex PCR and
automated gene scan analysis were conducted on DNA from 175 Australian
Anglo-Celtic Caucasian hypertensives. Statistical evaluation of genotype
data by nonparametric methods resulted in exclusion scores. In this
study, Wang et al. (1999) excluded AGT in the etiology of hypertension,
at least in the population of Australian Anglo-Celtic Caucasians
studied.

In a study of hypertensive patients, Nakajima et al. (1999) identified a
mutation at the -30 amino acid position of the angiotensinogen signal
peptide, in which an arginine was replaced by a proline (R-30P).
Heterozygous individuals with R-30P showed a tendency to lowered plasma
angiotensinogen levels compared with normal individuals in the family.
Because of the small number of family members available for study, a
possible relationship between the mutation and essential hypertension
could not be addressed. Human angiotensinogen mRNA has 2 in-phase
translation initiation codons (AUG) starting upstream 39 and 66
nucleotides from the cap site. R-30P occurs in a cluster of basic
residues adjacent to the first AUG codon that may affect intracellular
sorting of the nascent protein.

To dissect the genetic pathway of hypertension, Guo et al. (1999)
measured angiotensinogen in 685 members of 186 families from a rural
community in southwest Nigeria. Commingling and segregation analyses
were performed. A mixture of 2 and/or 3 distributions fitted the data
significantly better than a single distribution in commingling analysis,
suggesting a major gene effect. Segregation analysis confirmed that a
recessive major gene model for low values of angiotensinogen provided
the best fit to the data and about 13% of the variance was due to the
recessive gene segregation.

Nakajima et al. (2002) examined the potential impact of the G-A
polymorphism 6-bp upstream from the initiation site of transcription
(-6G-A; 106150.0002) on AGT promoter function. Screening an expression
library with a double-stranded DNA segment centered on -6 led to the
isolation of cDNA clones encoding the YB1 protein (NSEP1; 154030). The
specificity of the interaction of YB1 with the proximal promoter of AGT
was verified by Southwestern blotting and gel mobility shift assays. In
cotransfection experiments, YB1 reduced basal AGT promoter activity in a
dose-dependent manner. Although these observations suggested a possible
role for YB1 in modulating AGT expression, this function was thought
likely to occur in the context of complex interactions involving other
nuclear factors.

In a case-control study of 186 African American and 127 Caucasian
patients with hypertension and 156 African American and 135 Caucasian
normotensive controls, Markovic et al. (2005) found that subjects with
the AA or AG genotype of the -793A-G promoter SNP were significantly
more likely to have hypertension (OR = 1.88). Additionally, the
differences in haplotype frequency distributions between cases and
controls were significant at the 7% level for all 4 subgroups
(stratified by race and sex).

Gu et al. (2005) examined a hypothesis that multiple genetic variants in
the renin-angiotensin system act together in blood pressure regulation,
via intermediate phenotypes such as blood pressure reactivity. They
found that genetic variants in regulatory regions of the AGT gene showed
strong association with blood pressure reactivity.

- Association with Coronary Heart Disease

In a New Zealand study of 422 patients with documented coronary heart
disease and 406 controls without known coronary heart disease (matched
to cases by age and sex), Katsuya et al. (1995) concluded that the T235
of AGT is an independent risk factor that carries an approximately
2-fold increased risk of coronary heart disease. In that study, however,
ACE DD (106180.0001) is not associated with any detectable increase in
coronary heart disease risk.

- Association with Nonfamilial Structural Atrial Fibrillation

Tsai et al. (2004) analyzed polymorphisms of the AGT, ACE, and
angiotensin II type I receptor (AGTR1; 106165) genes in 250 patients
with documented nonfamilial structural atrial fibrillation and 250
controls matched for age, sex, presence of left ventricular dysfunction,
and presence of significant valvular heart disease. In multilocus
haplotype analysis, the AGT gene haplotype profile was significantly
different between cases and controls (p = 0.0002). In single-locus
analysis, the M235T, -6G-A, and -217G-A polymorphisms of the AGT gene
were significantly associated with atrial fibrillation. Significant
gene-gene interactions between the ACE insertion/deletion (106180.0001)
and AGT and AGTR1 polymorphisms were detected. Tsai et al. (2004)
concluded that renin-angiotensin system gene polymorphisms are
associated with nonfamilial structural atrial fibrillation.

- Association with Inflammatory Bowel Disease

Hume et al. (2006) analyzed 2 cohorts of Australian patients with
inflammatory bowel disease (see 266600) and sex- and age-matched
controls for the -6G-A promoter polymorphism of the AGT gene
(106150.0002) and found a significant association between the -6 AA
genotype and Crohn disease in 1 cohort (p = 0.007) and in the 2 cohorts
combined (p = 0.008).

- Association with Susceptibility to Microvascular Complications
of Diabetes 3

In a study of patients with insulin-dependent diabetes mellitus (IDDM;
222100) who had developed proliferative retinopathy (MVCD3, 612624),
Marre et al. (1997) found evidence of an interaction between the ACE I/D
(106180.0001) and AGT M235T (106150.0001) polymorphisms that could
account for the degree of renal involvement, although M235T was not
contributive alone.

BIOCHEMICAL FEATURES

- Crystal Structure

Zhou et al. (2010) solved the crystal structure of angiotensinogen to
2.1-angstrom resolution and showed that the angiotensin cleavage site is
inaccessibly buried in its amino-terminal tail. The conformational
rearrangement that makes this site accessible for proteolysis was
revealed in a 4.4-angstrom structure of the complex of human
angiotensinogen with renin (179820). The coordinated changes involved
are critically linked by a conserved but labile disulfide bridge. Zhou
et al. (2010) showed that the reduced unbridged form of angiotensinogen
is present in the circulation in a near 40:60 ratio with the oxidized
sulfydryl-bridged form, which preferentially interacts with
receptor-bound renin. Zhou et al. (2010) proposed that this
redox-responsive transition of angiotensinogen to a form that will more
effectively release angiotensin at a cellular level contributes to the
modulation of blood pressure. Specifically, Zhou et al. (2010)
demonstrated the oxidative switch of angiotensinogen to its more active
sulfydryl-bridged form in the maternal circulation in preeclampsia (see
189800).

ANIMAL MODEL

Tanimoto et al. (1994) generated angiotensinogen-deficient mice by
homologous recombination in mouse embryonic stem cells. These mice do
not produce angiotensinogen in the liver, resulting in the complete loss
of plasma immunoreactive angiotensin I. The systolic blood pressure of
the homozygous mutant mice was 66.9 +/- 4.1 mm Hg, as compared with
100.4 +/- 4.4 mm Hg in wildtype mice. The findings demonstrated an
indispensable role for the renin-angiotensin system in maintaining blood
pressure.

Ding et al. (2001) supplied human renin and the kidney-specific
angiotensinogen transgene to Agt -/- mice but could not rescue
lethality. Angiotensinogen protein and functional angiotensin II was
generated in the kidney, and the kidney-specific transgene was
temporally expressed during renal development similar to the endogenous
AGT gene. Ding et al. (2001) concluded that their data strongly support
the notion that the loss of systemic AGT, but not intrarenal AGT, is
responsible for death in the Agt -/- mouse model. Ding et al. (2001)
also concluded that the intrarenal renin-angiotensin system located in
the proximal tubule plays an important role in blood pressure regulation
and may cause hypertension if overexpressed, but may not be required for
continued development of the kidney after birth.

The angiotensinogen M235T polymorphism (106150.0001) in humans is linked
to differential expression of the AGT gene and hypertension. Kim et al.
(2002) investigated how mice responded to 5 genetically determined
levels of mouse Agt gene expression covering the range associated with
the M235T variants. By using high-throughput molecular phenotyping,
tissue RNAs were assayed for expression of 10 genes important in
hypertension. Significant positive and negative responses occurred in
both sexes as Agt expression increased 2-fold, including a 3-fold
increase in aldosterone synthase (ALDOS; 124080) expression in adrenal
gland, and a 2-fold decrease in renin expression in kidney. In males,
cardiac expression of the precursor of atrial natriuretic peptide B
(600295) and of adrenomedullin (ADM; 103275) also increased
approximately 2-fold. The relative expression of all genes studied,
except Agt, differed significantly in the 2 sexes, and several
unexpected relationships were encountered. The correlation between blood
pressure and liver Agt expression within the 5 Agt genotypes was
significant in females but not in males, whereas correlation of blood
pressure with differences between the genotypes was less in females than
in males. Kim et al. (2002) concluded that the marked gender differences
in gene expression in wildtype mice and the changes induced by moderate
alterations in Agt expression and blood pressure emphasized the need to
look for similar differences in humans.

Using a transgenic strategy, Lochard et al. (2003) restored angiotensin
II exclusively in the brains of Agt-deficient mice. Restoration of brain
angiotensin II corrected the hydronephrosis and partially corrected the
renal dysfunction associated with loss of Agt expression. Lochard et al.
(2003) concluded that the renin-angiotensin system affects renal
development and function through systemically accessible targets in the
brain.

Lautrette et al. (2005) found that angiotensin II infusion in mice over
2 months produced severe renal lesions, mainly glomerulosclerosis,
tubular atrophy and/or dilation with little microcyst formation, mild
interstitial fibrosis, and multifocal mononuclear cell infiltration. In
contrast, mice overexpressing a dominant-negative isoform of EGFR
(131550) were protected from renal lesions during chronic angiotensin II
infusion. Tgf-alpha (TGFA; 190170) and its sheddase, Tace (ADAM17;
603639), were induced by angiotensin II treatment, Tace was
redistributed to apical membranes, and Egfr was phosphorylated.
Angiotensin II-induced lesions were reduced in mice lacking Tgfa or in
mice given a Tace inhibitor. Inhibition of angiotensin II prevented Tgfa
and Tace accumulation and renal lesions after nephron reduction.
Lautrette et al. (2005) concluded that EGFR transactivation is crucial
for angiotensin II-associated renal deterioration.

In Ets1 (164720)-null mice, Zhan et al. (2005) observed significantly
reduced arterial wall thickening, perivascular fibrosis, and cardiac
hypertrophy compared to wildtype mice in response to angiotensin II. The
induction of 2 known targets of ETS1, CDKN1A (116899) and PAI1 (173360),
by angiotensin II was markedly blunted in the aorta of Ets1-null mice
compared with wildtype controls. Expression of MCP1 (CCL2; 158105) was
similarly reduced, resulting in significantly diminished recruitment of
T cells and macrophages to the vessel wall. Zhan et al. (2005) concluded
that ETS1 has a critical role as a transcriptional mediator of vascular
inflammation and remodeling in response to angiotensin II.

Frank et al. (2007) generated Myoz2 (605602)-overexpressing transgenic
mice, which did not exhibit a pathologic phenotype when unchallenged.
Long-term infusion of angiotensin II resulted in a similar degree of
hypertension in both transgenic and wildtype mice; in contrast to
wildtype, however, the Myoz2-overexpressing mice did not develop cardiac
hypertrophy, yet had no impairment of contractile function by cardiac
catheterization and echocardiography. Induction of the hypertrophic gene
program was markedly blunted and expression of the calcineurin-dependent
gene MCIP1 (RCAN1; 602917) was significantly reduced in transgenic mice.
Frank et al. (2007) concluded that the calsarcin-1 protein prevents
angiotensin II-induced cardiomyocyte hypertrophy at least in part via
inhibition of calcineurin signaling.

*FIELD* AV
.0001
HYPERTENSION, ESSENTIAL, SUSCEPTIBILITY TO
PREECLAMPSIA, SUSCEPTIBILITY TO, INCLUDED;;
IgA NEPHROPATHY, PROGRESSION TO RENAL FAILURE IN, SUSCEPTIBILITY TO,
INCLUDED
AGT, MET235THR

By 3 sets of observations--genetic linkage, allelic associations, and
differences in plasma angiotensinogen concentrations among AGT
genotypes--in a sample of families from 2 different populations, Salt
Lake City and Paris, Jeunemaitre et al. (1992) demonstrated involvement
of the AGT gene in essential hypertension. Hypertension showed
association with 2 distinct amino acid substitutions, M235T and T174M.
The 2 variants showed complete linkage disequilibrium; T174M occurred on
a subset of the haplotypes carrying the M235T variant, and both
haplotypes were observed at higher frequency among hypertensives.
Whether M235T directly mediates a predisposition to hypertension, or an
unidentified risk factor is common to both haplotypes, or each haplotype
harbors a distinct factor is uncertain.

Lifton et al. (1993) found the M235T variant to be very frequent among
African Americans who as a group have a high prevalence of hypertension.
The frequency of T235 homozygotes was 70%, with 28% for T235
heterozygotes and only 2% for M235 homozygotes; the corresponding
figures were 12%, 46%, and 42% in Caucasians. Lifton et al. (1993)
suggested that the T235 allele may have been the ancestral form, and, in
an earlier period of salt scarcity, increased salt and water retention
associated with T235 may have been an advantage. After the Diaspora from
Africa to salt-rich areas, M235 may have become fixed or had some
advantage.

Russ et al. (1993) described a rapid method for detection of the M235T
polymorphism.

It is well known that blood pressure increases faster over time in black
children than in white children and that in adults, hypertension is more
prevalent in blacks. In a study of 148 white and 62 black normotensive
children, Bloem et al. (1995) found that the frequency of the T235
allele was 0.81 in blacks and 0.42 in whites. The mean angiotensinogen
level was 19% higher in blacks than in whites. This racial difference in
the renin-angiotensin system may contribute to the disparity in blood
pressure levels in white and black young people.

In Rochester, Minnesota, Fornage et al. (1995) studied a
population-based sample consisting of 104 subjects diagnosed with
hypertension before age 60 and 195 matched normotensive individuals to
determine the relationship between M235T and essential hypertension. The
authors used 2 methods: contingency chi-square analysis of association
and a multivariable conditional logistic regression for variation at the
M235T polymorphism as a significant predictor of the probability of
having essential hypertension. They detected no statistically
significant association in either gender or in a subset of severely
hypertensive subjects requiring 2 or more antihypertensive medications.
Furthermore, variation in the number of M235T alleles made no
significant contribution to predicting the probability of having
hypertension, either alone or in conjunction with other predictor
variables. See also Niu et al. (1998).

Frossard et al. (1998) studied the association between the M235T and
T174M variants in residents of the United Arab Emirates (Emirati), an
ethnic group characterized by no alcohol intake and no cigarette
smoking. T174M showed no correlation with any of the 4 clinical entities
included in the study (essential hypertension, left ventricular
hypertrophy, ischemic heart disease, and myocardial infarction), but the
T235 allele occurred more frequently in the essential hypertension group
and less frequently in the group of myocardial infarction survivors.
They also found that the T235 allele frequencies decreased with age,
suggesting that in the Emirati population, T235 alleles are associated
with a reduced life span.

Preeclampsia Susceptibility

In a series of Caucasian women with pregnancy-induced hypertension, Ward
et al. (1993) observed significant association of preeclampsia (see
189800) with the M235T variant. The finding was corroborated in a sample
ascertained in Japan. Arngrimsson et al. (1993) studied involvement of
the ATG gene in preeclampsia and eclampsia by linkage studies with a
highly informative dinucleotide repeat from the 3-prime flanking region
of the ATG gene. They used a nonparametric method, i.e., one in which
the mode of inheritance, gene frequency, and penetrance did not have to
be specified. Their results supported the findings of Ward et al.
(1993).

In a study of 150 'coloured' South African patients, 50 with normal
pregnancies, 50 with severe preeclampsia, and 50 with abruptio
placentae, Hillermann et al. (2005) found no association between the
M235T variant of the AGT gene and preeclampsia or abruptio placentae.

Progression to Renal Failure in IgA Nephropathy

Studying the met235-to-thr polymorphism of the AGT gene in 168 Caucasian
patients with IgA nephropathy (161950), Pei et al. (1997) found that
patients with the AGT MT (79) and TT (29) genotypes had a faster rate of
deterioration of creatinine clearance than those with the MM (60)
genotype. Similarly, patients with AGT MT and TT genotypes had higher
maximal values of proteinuria than those with the MM genotype.
Multivariant analysis detected an interaction between the AGT and ACE
gene polymorphisms, with the presence of ACE/DD polymorphism
(106180.0001) adversely affecting disease progression only in patients
with the AGT/MM genotype. Neither of these gene polymorphisms was
associated with systemic hypertension. Thus, Pei et al. (1997) suggested
that polymorphisms at the AGT and ACE gene loci are important markers
for predicting progression to chronic renal failure in Caucasian
patients with IgA nephropathy.

.0002
HYPERTENSION, ESSENTIAL, SUSCEPTIBILITY TO
CROHN DISEASE, ASSOCIATION WITH, INCLUDED
AGT, -6A HAPLOTYPE

Inoue et al. (1997) found that a common variant in the proximal promoter
of the ATG gene, an adenine instead of a guanine 6 bp upstream from the
site of transcription initiation (-6G-A), is in very tight linkage
disequilibrium with T235 (106150.0001) and marks the original form of
the gene. Tests of promoter function in cultured cells and studies of
binding between AGT oligonucleotides and nuclear proteins strongly
suggested that the substitution at nucleotide -6 affects specific
interactions between at least 1 trans-acting nuclear factor and the
promoter of AGT, thereby influencing the basal rate of transcription of
the gene. These observations suggested a biologic mechanism by which
individual differences in the AGT gene may predispose carriers to the
development of essential hypertension. They also suggested an
evolutionary scenario to account for the emergence of common human
disorders, which may fit the 'thrifty genotype' hypothesis advanced by
Neel (1962). See Neel et al. (1998) for an update on this hypothesis.

The geographic distribution of the A allele of the -6G-A polymorphism in
the AGT gene leads to the hypothesis that the G allele has been
selectively advantageous outside Africa. To test this hypothesis,
Nakajima et al. (2004) investigated the roles of population history and
natural selection in shaping patterns of genetic diversity in AGT by
sequencing the entire AGT gene (14,400 bp) in 736 chromosomes from
Africa, Asia, and Europe. They found that the A allele was present at
higher frequency in African populations than in non-African populations.
Neutrality tests found no evidence of a departure from selective
neutrality, when whole AGT sequences were compared. However, tests
restricted to sites in the vicinity of the -6G-A polymorphism found
evidence of a selective sweep. Sliding window analyses showed that
evidence of the sweep was restricted to sites in tight linkage
disequilibrium with the -6G-A polymorphism. Furthermore, haplotypes
carrying the G allele showed elevated levels of linkage disequilibrium,
suggesting that they have risen to high frequency relatively recently
(the G allele was estimated to have arisen 22,500 to 44,500 years ago).
Departures from neutral expectation in some but not all regions of AGT
indicated that patterns of diversity in the gene cannot be accounted for
solely by population history, which would affect all regions equally.
Taken together, patterns of genetic diversity in AGT suggested that
natural selection has generally favored the G allele over the A allele
in non-African populations.

In a study of 2 cohorts of Australian patients with inflammatory bowel
disease (see 266600) and age- and sex-matched controls, Hume et al.
(2006) found that the AGT -6 A/A genotype was significantly associated
with Crohn disease in 1 cohort and in the 2 cohorts combined (p = 0.007
and p = 0.008, respectively). TDT analysis of 148 Crohn families showed
moderately significant overtransmission of the variant A allele (p =
0.03).

Jain et al. (2010) presented evidence that the SNP at -6 of the AGT gene
is a haplotype marker rather than a functional polymorphism. They
identified 3 additional SNPs in the promoter region of the AGT gene at
positions -1670, -1562, and -1561. Variants -1670A, -1562C, and -1561T
almost always occurred with -6A and were designated the -6A haplotype,
and variants -1670G, -1562G, and -1561G almost always occurred with -6G
and were designated -6G haplotype. Chromatin immunoprecipitation
analysis showed that both HNF1-alpha (HNF1A; 142410) and glucocorticoid
receptor (GR, or GCCR; 138040) had higher affinity for the -6A haplotype
than the -6G haplotype. Within the -6A haplotype, HNF1-alpha
preferentially bound sequence around -1670A, and GR preferentially bound
sequence containing -1562C and -1561T. An intact HNF1 site was required
for GR-induced promoter activity in vitro. Jain et al. (2010) engineered
transgenic mice expressing human BACs covering 116 kb of the 5-prime
flanking region of the AGT gene of either haplotype, plus all 5 exons
and 4 introns and 54 kb of the 3-prime flanking region. Mice expressing
the human AGT gene of the -6A haplotype showed increased plasma AGT
levels and increased blood pressure compared with mice expressing the
-6G haplotype.

.0003
RENAL TUBULAR DYSGENESIS
AGT, ARG375GLN

In a consanguineous family of Turkish derivation with renal tubular
dysgenesis (267430), Gribouval et al. (2005) found an arg375-to-gln
(R375Q) mutation in the AGT gene. The nucleotide substitution, 1124G-A,
involved the last nucleotide of exon 3. Two sisters were involved in
this family reported by Kemper et al. (2001). One sister survived after
several days of anuria; she had severe and persistent hypotension at
birth, requiring fluid infusion, adrenaline, and dopamine treatment. Her
sister, who died at 4 days of life, also had very low blood pressure.

.0004
RENAL TUBULAR DYSGENESIS
AGT, GLU202TER

In a Japanese female infant with renal tubular dysgenesis (267430),
Uematsu et al. (2006) identified compound heterozygosity for 2 mutations
in the AGT gene: a 604C-T transition in exon 2, resulting in a
glu202-to-ter (E202X) substitution, and a 1-bp deletion (1290delT;
106150.0005) in exon 5, resulting in a frameshift and a premature stop
codon at position 454. The patient was born at 35 weeks gestation with
Potter syndrome, hypoplastic lungs, and severe hypotension. Treatment
with fresh frozen plasma and peritoneal dialysis resulted in clinical
improvement and she had spontaneous urination at day 29. At age 18
months, she had no obvious motor or mental retardation. An older brother
with similar features had died a few days after birth.

Gribouval et al. (2012) stated that the frameshift and premature stop
caused by the 1290delT mutation was phe430leufsX25.

.0005
RENAL TUBULAR DYSGENESIS
AGT, 1-BP DEL, 1290T

See 106150.0004 and Uematsu et al. (2006).

*FIELD* SA
Arakawa et al. (1968)
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45. Nakajima, T.; Inoue, I.; Cheng, T.; Lalouel, J.-M.: Molecular
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47. Nakajima, T.; Wooding, S.; Sakagami, T.; Emi, M.; Tokunaga, K.;
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J.; Hayasaka, I.; Ishida, T.; Saitou, N.; Pavelka, K.; Lalouel, J.-M.;
Jorde, L. B.; Inoue, I.: Natural selection and population history
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51. Ohkubo, H.; Kageyama, R.; Ujihara, M.; Hirose, T.; Inayama, S.;
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52. Pei, Y.; Scholey, J.; Thai, K.; Suzuki, M.; Cattran, D.: Association
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2010.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2013
Patricia A. Hartz - updated: 11/10/2011
Ada Hamosh - updated: 1/4/2011
Marla J. F. O'Neill - updated: 2/13/2009
Marla J. F. O'Neill - updated: 3/7/2008
Marla J. F. O'Neill - updated: 12/4/2007
Patricia A. Hartz - updated: 3/1/2007
Cassandra L. Kniffin - updated: 12/21/2006
Victor A. McKusick - updated: 6/20/2006
Marla J. F. O'Neill - updated: 3/30/2006
Marla J. F. O'Neill - updated: 12/7/2005
Marla J. F. O'Neill - updated: 11/16/2005
Victor A. McKusick - updated: 9/27/2005
Patricia A. Hartz - updated: 9/12/2005
John A. Phillips, III - updated: 10/11/2004
Victor A. McKusick - updated: 4/23/2004
Marla J. F. O'Neill - updated: 3/24/2004
Patricia A. Hartz - updated: 3/3/2003
Victor A. McKusick - updated: 10/1/2002
Victor A. McKusick - updated: 2/11/2002
Victor A. McKusick - updated: 1/22/2002
John A. Phillips, III - updated: 8/8/2001
Ada Hamosh - updated: 4/19/2001
Victor A. McKusick - updated: 6/7/2000
Victor A. McKusick - updated: 1/14/2000
Victor A. McKusick - updated: 11/23/1999
John A. Phillips, III - updated: 3/19/1999
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 1/25/1999
Victor A. McKusick - updated: 1/27/1998
Victor A. McKusick - updated: 5/27/1997
Victor A. McKusick - updated: 4/28/1997

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

*FIELD* ED
carol: 05/02/2013
ckniffin: 5/1/2013
terry: 6/4/2012
mgross: 2/8/2012
terry: 11/10/2011
terry: 10/13/2011
joanna: 10/5/2011
alopez: 1/5/2011
terry: 1/4/2011
terry: 12/8/2010
carol: 2/19/2009
carol: 2/13/2009
wwang: 10/14/2008
terry: 9/25/2008
carol: 9/24/2008
carol: 3/7/2008
carol: 12/6/2007
carol: 12/5/2007
terry: 12/4/2007
alopez: 10/3/2007
mgross: 5/21/2007
mgross: 3/1/2007
wwang: 1/22/2007
ckniffin: 12/21/2006
alopez: 12/6/2006
wwang: 6/20/2006
terry: 6/20/2006
wwang: 4/3/2006
terry: 3/30/2006
carol: 12/7/2005
terry: 12/7/2005
wwang: 11/18/2005
terry: 11/16/2005
alopez: 9/28/2005
terry: 9/27/2005
mgross: 9/12/2005
alopez: 6/8/2005
alopez: 1/5/2005
alopez: 10/12/2004
alopez: 10/11/2004
tkritzer: 4/28/2004
terry: 4/23/2004
tkritzer: 3/29/2004
terry: 3/24/2004
mgross: 3/3/2003
tkritzer: 10/1/2002
terry: 3/13/2002
mgross: 2/13/2002
terry: 2/11/2002
carol: 2/4/2002
mcapotos: 1/31/2002
terry: 1/22/2002
alopez: 8/8/2001
alopez: 4/20/2001
terry: 4/19/2001
carol: 9/14/2000
mcapotos: 6/28/2000
terry: 6/7/2000
mcapotos: 2/1/2000
mcapotos: 1/28/2000
terry: 1/14/2000
carol: 11/29/1999
terry: 11/23/1999
terry: 4/30/1999
mgross: 3/24/1999
mgross: 3/19/1999
terry: 3/12/1999
carol: 1/25/1999
mark: 2/3/1998
terry: 1/27/1998
mark: 12/8/1997
joanna: 6/23/1997
jenny: 5/30/1997
terry: 5/27/1997
alopez: 4/28/1997
terry: 4/25/1997
mark: 10/11/1996
mark: 3/28/1996
terry: 3/20/1996
mark: 9/19/1995
carol: 1/30/1995
jason: 7/14/1994
pfoster: 3/25/1994
mimadm: 2/11/1994
carol: 12/16/1993

MIM 145500
*RECORD*
*FIELD* NO
145500
*FIELD* TI
#145500 HYPERTENSION, ESSENTIAL
;;EHT
*FIELD* TX
A number sign (#) is used with this entry because variations in many
read moregenes contribute to essential hypertension. For information on genetic
heterogeneity of essential hypertension, see the MAPPING section.

DESCRIPTION

The Pickering school held that blood pressure has a continuous
distribution, that multiple genes and multiple environmental factors
determine the level of one's blood pressure just as the determination of
stature and intelligence is multifactorial, and that 'essential
hypertension' is merely the upper end of the distribution (Pickering,
1978). In this view the person with essential hypertension is one who
happens to inherit an aggregate of genes determining hypertension (and
also is exposed to exogenous factors that favor hypertension). The Platt
school took the view that essential hypertension is a simple mendelian
dominant trait (Platt, 1963). McDonough et al. (1964) defended the
monogenic idea. See McKusick (1960) and Kurtz and Spence (1993) for
reviews. Swales (1985) reviewed the Platt-Pickering controversy as an
'episode in recent medical history.' The Pickering point of view appears
to be more consistent with the observations.

CLINICAL FEATURES

Ravogli et al. (1990) measured blood pressure in 15 normotensive
subjects whose parents were both hypertensive (FH+/+), 15 normotensive
subjects with 1 hypertensive parent (FH +/-), and 15 normotensive
subjects whose parents were not hypertensive (FH -/-); among the 3
groups, subjects were matched for age, sex, and body mass index. The
measurements were made in the office during a variety of laboratory
stressors and during a prolonged rest period, and ambulatory blood
pressure monitoring was done for a 24-hour period. Office blood pressure
was higher in the FH +/+ group than in the FH -/- group. The pressor
responses were similar in the 2 groups, but the FH +/+ group had higher
prolonged 24-hour blood pressure than the FH -/- group; the differences
were always significant at the 5% level for systolic blood pressure. The
FH +/+ group also had a greater left ventricular mass index by
echocardiography than the FH -/- group. The blood pressure values and
echocardiographic values of the FH +/- group tended to lie between those
of the other 2 groups. Thus, the higher blood pressure shown by
individuals in the prehypertensive stage with a family history of
parental hypertension does not reflect a hyperreactivity to stress but
an early permanent blood pressure elevation. See comments by Pickering
(1990), the son of the early defender of the multifactorial hypothesis.

In a comparison of normotensive subjects who had either hypertensive or
normotensive parents, van Hooft et al. (1991) found that the mean renal
blood flow was lower in subjects with 2 hypertensive parents than in
those with 2 normotensive parents. Moreover, both the filtration
fraction and renal vascular resistance were higher in the subjects with
2 hypertensive parents. The subjects with 2 hypertensive parents had
lower plasma concentrations of renin (179820) and aldosterone than those
with 2 normotensive parents. The values in subjects with one
hypertensive and one normotensive parent fell between those for the
other 2 groups. The conclusion of van Hooft et al. (1991) was that
alterations in renal hemodynamics occur at an early stage in the
development of familial hypertension.

Examination of the biochemical processes that effect blood pressure
homeostasis should elucidate some of the interactive physiologic
regulators that malfunction in persons with elevated pressure and show
whether single genes of large effect are important in some. For example,
the electrochemical gradients of cations across erythrocyte membranes
are maintained by at least 7 pathways. Garay and Meyer (1979)
demonstrated an abnormally low ratio of Na+ to K+ net fluxes in
sodium-loading and potassium-depleted erythrocytes of human essential
hypertension. This finding was absent in normotensive families and in
secondary hypertension, but present in some young normotensive children
of hypertensive parents.

Garay et al. (1980) found that erythrocytes have a Na, K-cotransport
system (independent of the pump) that extrudes both internal Na and K
and is functionally deficient in red cells of persons with essential
hypertension and some of their descendants, with or without
hypertension. Parfrey et al. (1981) showed that whereas young adults
with a familial predisposition to hypertension behave similarly to those
without such a predisposition in having a pressor response to a high
sodium intake, they are peculiar in showing a depressor response to a
high potassium intake. Garay (1981) found a defect in the
furosemide-sensitive Na-K cotransfer mechanism in red cells of patients
with essential hypertension and in some of their normotensive relatives.
The same defect is found in strains of experimental animals bred for
susceptibility to salt-induced hypertension or spontaneous hypertension.

Etkin et al. (1982) assessed red cell sodium transport simply by
measuring the unidirectional passive influx of sodium-22 into
ouabain-treated erythrocytes. In American blacks with essential
hypertension, this approach failed to show the abnormal erythrocyte
sodium transport that is characteristic of white persons with essential
hypertension. Thus, among American blacks, essential hypertension may
have a different genetic basis. De Wardener and MacGregor (1982)
reviewed evidence for the hypothesis that 'the underlying genetic lesion
is a renal difficulty in excreting sodium,' which sets in train a rise
in the circulating concentration of a sodium-transport inhibitor.

Canessa et al. (1980) found ouabain-insensitive erythrocyte
sodium-lithium countertransport (SLC) to be at least 2-fold elevated in
patients. Woods et al. (1982) confirmed these results and further showed
that normotensive sons of patients had significantly higher rates of
countertransport than sons of normotensive controls. In patients with a
positive family history, Clegg et al. (1982) found raised lithium efflux
in 76% and raised red cell sodium content in 36%. Heagerty et al. (1982)
measured sodium efflux rates in leukocytes in 18 normotensive subjects
who had one or more first-degree relatives with essential hypertension.
The total efflux rate constant was significantly lower, owing to reduced
ouabain-sensitive sodium pump activity.

Woods et al. (1983) demonstrated that the rate of sodium-lithium
countertransport may not be a wholly intrinsic feature of the red cell;
a dialyzable plasma factor could be demonstrated. In a study of white
males, Weder (1986) found that lithium clearance, a measure of proximal
tubular reabsorption of sodium, was reduced and red-cell lithium-sodium
countertransport was increased in hypertensives as compared with
normals. Within the group of normotensive controls, lithium clearance
was lower in those with at least 1 first-degree relative with
hypertension than in those with no hypertensive relative. Weder (1986)
concluded that enhanced proximal tubular sodium reabsorption may precede
the development of essential hypertension.

Kagamimori et al. (1985) found a significant correlation in
lithium-sodium countertransport and sodium-potassium cotransport rates
in red blood cells in parent-offspring pairs (r = 0.52, p less than
0.01, and r = 0.46, p less than 0.01, respectively) but not in
husband-wife pairs. Sodium pump rates, on the other hand, were
significantly correlated in both pairs. This led them to conclude that
sodium pump has a substantial environmental component whereas the
genetic component predominates in the other functions. This conclusion
was supported by the fact that sodium pump rates correlated
significantly with sodium/creatinine and sodium/potassium ratios in
casual urine. Hasstedt et al. (1988) presented evidence supporting the
possibility that an allele at a major locus elevates the rate of
sodium-lithium countertransport. Rebbeck et al. (1991) found evidence of
both environmental and genetic factors in the determination of
sodium-lithium countertransport.

Parmer et al. (1992) assessed baroreflex sensitivity in hypertensives
with or without a positive family history of hypertension and in
normotensives with or without a positive family history. This was done
by recording cardiac slowing in response to acute phenylephrine-induced
hypertension and cardiac acceleration in response to amyl
nitrite-induced fall in blood pressure. Of all variables investigated,
family history of hypertension was the strongest unique predictor of
baroreflex sensitivity. Parmer et al. (1992) suggested that impairment
in baroreflex sensitivity in hypertension is in part genetically
determined and may be an important hereditary component in the
pathogenesis of essential hypertension.

Low birth weight is associated with the subsequent development of
hypertension in adult life. Maternal malnutrition has been suggested as
the cause. Edwards et al. (1993) suggested an alternative etiology,
namely, increased fetal exposure to maternal glucocorticoids.
Benediktsson et al. (1993) pointed out that hypertension is strongly
predicted by the combination of low birth weight and a large placenta.
Normally, fetal protection is afforded by placental
11-beta-hydroxysteroid dehydrogenase (218030), which converts
physiologic glucocorticoids to inactive products.

Siffert et al. (1995) and Pietruck et al. (1996) demonstrated an
enhanced signal transduction via pertussis toxin-sensitive G proteins in
lymphoblasts and fibroblasts from selected patients with essential
hypertension.

Noon et al. (1997) studied 105 men, aged 23 to 33 years, drawn at random
from the population studied by Medical Research Council Working Party
(1985). In hypertensive subjects with hypertensive parents, Noon et al.
(1997) reported impaired dermal vasodilatation and fewer capillaries on
the dorsum of the finger, as compared to these factors in hypertensive
subjects with hypotensive parents or hypotensive subjects with either
hypo- or hypertensive parents. No differences in other hemodynamic
indices were seen among the groups. Noon et al. (1997) suggested that
defective angiogenesis may be an etiological component in the
inheritance of hypertension.

- Salt-Sensitive Essential Hypertension

Several varieties of familial, salt-sensitive, low-renin hypertension
with a proven or presumptive genetic basis have been described (Gordon,
1995). The conditions in which the molecular basis of the disorder has
been identified at the DNA level include 2 forms of Liddle syndrome
(177200) due to mutation in the beta subunit (600760.0001) or gamma
subunit (600761.0001) of the amiloride-sensitive epithelial sodium
channel; the syndrome of apparent mineralocorticoid excess (AME) due to
a defect in the renal form of 11-beta-hydroxysteroid dehydrogenase
(218030); and the form of familial hyperaldosteronism which is
successfully treated with low doses of glucocorticoids, such as
dexamethasone ('glucocorticoid-remediable aldosteronism'), which is due
to a Lapore hemoglobin-like fusion of the contiguous CYP11B1 (610613)
and CYP11B2 (124080) genes.

In studies in rats, Machnik et al. (2009) demonstrated that TONEBP
(604708)-VEGFC (601528) signaling in mononuclear phagocytes is a major
determinant of extracellular volume and blood pressure homeostasis, and
that VEGFC is an osmosensitive, hypertonicity-driven gene intimately
involved in salt-induced hypertension.

- Syndromic Forms of Hypo- and Hypertension

Lifton (1996) reviewed the molecular genetics of human blood pressure
variation. He pointed out that at least 10 genes have been shown to
alter blood pressure; most of these are rare mutations imparting large
quantitative effects that either raise or lower blood pressure. These
mutations alter blood pressure through a common pathway, changing salt
and water reabsorption in the kidney. Disorders that fall into this
category include glucocorticoid remediable aldosteronism (103900), the
syndrome of apparent mineralocorticoid excess (218030), and Liddle
syndrome (177200), which is known to be caused by a mutation in either
the beta subunit or the gamma subunit of the renal epithelial sodium
channel. Unlike the preceding conditions, hypotension characterizes the
following mendelian disorders: pseudohypoaldosteronism type 1 (264350),
which can be produced by mutation in either the alpha subunit (600228)
or the beta subunit (600760) of the same epithelial sodium channel
involved in Liddle syndrome; and Gitelman syndrome (263800), which is
caused by mutations in the thiazide-sensitive Na-Cl cotransporter
(600968).

Lifton et al. (2001) reviewed rare syndromic forms of hyper- and
hypotension showing mendelian inheritance, for some of which the
underlying mutations have been identified by positional cloning and
candidate gene analyses. These genes all regulate renal salt
reabsorption, in accordance with the work of Guyton (1991) and others
that established that the kidney plays a central role in blood pressure
regulation.

INHERITANCE

Hasstedt et al. (1988) measured red cell sodium in 1,800 normotensive
members of 16 Utah pedigrees ascertained through hypertensive or
normotensive probands, sibs with early stroke death, or brothers with
early coronary disease. Likelihood analysis suggested that RBC sodium
was determined by 4 alleles at a single locus, each allele being
recessive to all alleles associated with a lower mean level. The 4
resultant distributions occurred in the following frequencies: 0.8%,
89.3%, 9.7%, and 0.2% with corresponding means for sodium level (mmol/1
RBC) of 4.32, 6.67, 9.06, and 12.19, respectively. The major locus was
thought to explain 29% of the variance in red cell sodium; polygenic
inheritance explained another 54.6%. A higher frequency of the high red
cell sodium genotype in pedigrees in which the proband was hypertensive
rather than normotensive provided evidence that this major locus
increases susceptibility to hypertension.

From a study of systolic blood pressure in 278 pedigrees ascertained
through children enrolled in the Rochester, Minnesota, school system,
Perusse et al. (1991) obtained results suggesting that variability in
systolic blood pressure is influenced by major effects of allelic
variation of a single gene, with gender and age dependence. They
suggested that a single gene may be associated with a steeper increase
of blood pressure with age among males and females.

MAPPING

Chromosome 1p36.1

Funke-Kaiser et al. (2003) proposed that the ECE1 gene (600423) on
chromosome 1p36.1 is a candidate for human blood pressure regulation and
identified 5 polymorphisms in ECE1 among a cohort of 704 European
hypertensive patients. In 100 untreated hypertensive women, both the
-338A (600423.0002) and -839G (600423.0003) alleles were significantly
associated with ambulatory blood pressure values.

Chromosome 1q42-43

Jeunemaitre et al. (1992) presented evidence of genetic linkage between
the angiotensinogen gene (AGT; 106150) and hypertension in humans,
demonstrated association of AGT molecular variants with the disease, and
found significant differences in plasma concentrations of
angiotensinogen among hypertensive subjects with different AGT
genotypes. Using the affected-pedigree-member method of linkage analysis
in 63 white European families in which 2 or more members had essential
hypertension, Caulfield et al. (1994) found evidence of linkage and
association of the AGT gene locus with essential hypertension.

Lifton (1996) commented on the fact that of the small number of
candidate genes examined for possible involvement in hypertension, only
the gene encoding angiotensinogen has met relatively stringent criteria
supporting its role in the pathogenesis of essential hypertension.
Secreted by the liver, angiotensinogen undergoes sequential cleavage by
renin and angiotensin I-converting enzyme to produce the active hormone
angiotensin II, which promotes the rise in blood pressure.

Chromosome 2p25-p24 (HYT3; 607329)

Angius et al. (2002) found evidence for linkage of an essential
hypertension susceptibility locus, HYT3, to chromosome 2p25-p24.

Chromosome 3p14.1-q12.3 (HYT7; 610948)

By performing a metaanalysis of genomewide scans for blood pressure
variation and hypertension in Caucasians using the genome-search
metaanalysis method (GSMA), Koivukoski et al. (2004) found strong
evidence of linkage to chromosome 3p14.1-q12.3.

Chromosome 3q21-q25

Bonnardeaux et al. (1994) identified an association between hypertension
and several polymorphisms in the AGTR1A gene (106165) on chromosome
3q21-q25.

Chromosome 4p12

Missense variants in the CORIN gene (605236) that impair CORIN function
have been associated with hypertensive risk in African Americans (Dries
et al., 2005; Wang et al., 2008).

Dong et al. (2013) identified a missense mutation in the CORIN gene
(R539C; 605236.0003) that caused impaired activity and appeared to
segregate with hypertension in a Han Chinese family.

Chromosome 4p16.3

A polymorphism in the gene encoding adducin-1 (ADD1; 102680.0001) on
chromosome 4p16.3 has been associated with salt-sensitive essential
hypertension.

Chromosome 5p (HYT6; 610262)

Wallace et al. (2006) found evidence for linkage with hypertension and
the covariates of lean body mass (HYT5; 610261) and high renal function
(HYT6) on chromosomes 20q and 5p, respectively.

Chromosome 5q34

Resistance to diastolic hypertension (608622) has been associated with
variation in the KCNMB1 gene (603951) on chromosome 5q34.

Chromosome 7q22.1

A polymorphism in the CYP3A5 gene (605325.0001) on chromosome 7q22.1 has
been associated with salt sensitivity in patients with essential
hypertension.

Chromosome 7q36

A mutation in the NOS3 gene (163729.0001) on chromosome 7q36 has been
associated with resistance to conventional therapy for essential
hypertension and with pregnancy-induced hypertension.

Chromosome 12p (HYT4; 608742)

In a genomewide scan of a large Chinese family with primary
hypertension, Gong et al. (2003) reported significant linkage to
chromosome 12p.

See also brachydactyly with hypertension (112410), which was shown by
Schuster et al. (1996) to map to chromosome 12p in a large Turkish
kindred. The disorder mapped within a region defined by markers D12S364
and D12S87.

Chromosome 12p13

Siffert et al. (1998) detected a novel polymorphism (825C-T) in exon 10
of the gene encoding the beta-3 subunit of heterotrimeric G proteins
(GNB3; 139130) on chromosome 12p13; see 139130.0001. The T allele was
associated with the occurrence of a splice variant, GNB3-s (encoding
G-beta-3-s), in which the nucleotides 498-620 of exon 9 are deleted.
This in-frame deletion caused the loss of 41 amino acids and 1 WD repeat
domain of the G-beta subunit. By Western blot analysis, the splice
variant appeared to be predominantly expressed in cells from individuals
carrying the T allele. The behavior of insect cells expressing the
splice variant indicated that it is biologically active. Genotype
analysis of 427 normotensive and 426 hypertensive subjects suggested a
significant association of the T allele with essential hypertension.

Chromosome 15q (HYT2; 604329)

Xu et al. (1999) detected significant linkage of essential hypertension
to the telomeric end of 15q in lower extreme diastolic blood pressure
sib pairs.

Chromosome 17cen-q11

In an analysis of 177 affected sib pairs, Rutherford et al. (2001)
provided evidence for the location of at least 1 hypertension
susceptibility locus on chromosome 17. Significant excess allele sharing
showed linkage to marker D17S949 on chromosome 17q22-q24; significant
allele sharing was also indicated for another marker, D17S799, located
close to the centromere. Since these 2 genomic regions are well
separated, the results indicated that there may be more than 1
chromosome 17 locus affecting human blood pressure. Rutherford et al.
(2001) concluded that the NOS2A (163730) gene, which encodes inducible
nitric oxide synthase and maps to chromosome 17cen-q11, may play a role
in essential hypertension. A polymorphism within the promoter of the
gene showed increased allele sharing among sib pairs and positive
association of NOS2A to essential hypertension.

Chromosome 17q (HYT1; 603918)

One of the principal blood pressure loci identified in experimental
hereditary hypertension in the rat has been mapped to chromosome 10.
Julier et al. (1997) investigated the homologous region on human
chromosome 17 in familial essential hypertension. Affected sib-pair
analysis and parametric analysis with ascertainment correction gave
significant evidence of linkage (p less than 0.0001 in some analyses)
near 2 closely linked microsatellite markers, D17S183 and D17S934, that
reside 18 cM proximal to the ACE locus. The authors concluded that 17q
contains a susceptibility locus (603918) for human hypertension
presumably separate from ACE and argued that comparative mapping may be
a useful approach for identification of such loci in humans.

By testing a series of microsatellite markers in the region identified
by Julier et al. (1997), Baima et al. (1999) confirmed the location of a
blood pressure QTL on 17q in a collection of both white and black sib
pairs in the U.S.

In an analysis of 177 affected sib pairs, Rutherford et al. (2001)
provided evidence for the location of at least 1 hypertension
susceptibility locus on chromosome 17. Significant excess allele sharing
showed linkage to marker D17S949 on chromosome 17q22-q24; significant
allele sharing was also indicated for another marker, D17S799, located
close to the centromere. Since these 2 genomic regions are well
separated, the results indicated that there may be more than 1
chromosome 17 locus affecting human blood pressure. Rutherford et al.
(2001) concluded that the NOS2A (163730) gene, which encodes inducible
nitric oxide synthase and maps to chromosome 17cen-q11, may play a role
in essential hypertension. A polymorphism within the promoter of the
gene showed increased allele sharing among sib pairs and positive
association of NOS2A to essential hypertension.

Chromosome 18q21 (HYT8; 611014)

In a case-control study of essential hypertension showing linkage to
chromosome 18q21 in Spanish patients, Guzman et al. (2006) observed
significant overrepresentation of a 2-SNP MEX3C (611005) haplotype, G at
dbSNP rs1941958 and T at dbSNP rs1893379, in hypertensive patients
compared with controls. Guzman et al. (2006) concluded that MEX3C
contributes to essential hypertension in Spanish patients.

Chromosome 20q (HYT5; 610261)

Wallace et al. (2006) found evidence for linkage with hypertension and
the covariates of lean body mass and high renal function on chromosomes
20q (HYT5) and 5p (HYT6; 610262), respectively.

Chromosome 20q13

Nakayama et al. (2002) identified a mutation in the PTGIS gene
(601699.0001), which maps to chromosome 20q13, in 3 sibs with essential
hypertension.

- Pending Linkage and Association Studies

Chromosome 1p36.3-p36.2

Tumor necrosis factor receptor-2 (TNFRSF1B; 191191) has been implicated
in insulin resistance and metabolic syndrome disorders such as
hypertension. Glenn et al. (2000) tested markers in and near the TNFR2
locus for linkage and association with hypertension as well as
hypercholesterolemia and plasma levels of the shed soluble receptor
(sTNF-R2). Using sib-pair analysis, they reported a sharp, significant
linkage peak centered at TNFRSF1B (multipoint maximum lod score = 2.6
and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively). In a
case-control study, they demonstrated a possible association of TNFRSF1B
with hypertension by haplotype analysis. Plasma sTNF-R2 was
significantly elevated in hypertensives and showed a correlation with
systolic and diastolic blood pressure. A genotypic effect of TNFRSF1B on
plasma sTNF-R2, as well as total, low, and high density lipoprotein
cholesterol, and diastolic blood pressure was also observed. The authors
proposed a scheme for involvement of TNF (see 191160) and its receptors
in hypertension and hypercholesterolemia.

Chromosome 1p33

Gainer et al. (2005) found an association between the 8590C variant of
the CYP4A11 gene (601310) on chromosome 1p33 and essential hypertension
in white individuals.

Chromosome 1q23

By genomewide linkage and candidate gene-based association studies,
Chang et al. (2007) demonstrated a replicated linkage peak for blood
pressure regulation on human chromosome 1q23, homologous to mouse and
rat quantitative trait loci (QTLs) for BP, that contains at least 3
genes associated with blood pressure levels in multiple samples: ATP1B1
(182330), RGS5 (603276), and SELE (131210). Chang et al. (2007) viewed
the probable relationship between each of these genes and blood pressure
regulation.

Chromosome 1q32

In a Chinese population in Taiwan, Chiang et al. (1997) found an
association between the renin gene (179820) HindIII polymorphism on
chromosome 1q32 and hypertension.

Chromosome 1q43

Zhang et al. (2004) studied 726 hypertensive Chinese patients and their
families for the association between the asp919-to-glu (D919G)
polymorphism of the MTR gene (156570) on chromosome 1q43 and the
antihypertensive effect of the angiotensin-converting enzyme (ACE;
106180) inhibitor benazepril. Compared to the 919D allele, both
population-based and family-based association tests demonstrated that
the 919G allele was associated with a significantly less diastolic blood
pressure reduction. No significant association was found between the
extent of systolic blood pressure reduction and benazepril therapy.

Chromosome 5q15

Yamamoto et al. (2002) screened the ALAP gene (ERAP1; 606832) gene for
mutations in 488 unrelated Japanese individuals and identified one
polymorphism, lys528 to arg (K528R), that showed an association with
essential hypertension. The estimated odds ratio for essential
hypertension was 2.3 for presence of the arg allele at codon 528, in
comparison with presence of the lys/lys genotype (p of 0.004).

Chromosome 6q24.3

As a complement to linkage and candidate gene association studies, Zhu
et al. (2005) carried out admixture mapping using genome scan
microsatellite markers among the African American participants in the
U.S. National Heart, Lung, and Blood Institute's Family Blood Pressure
Program. This population was assumed to have experienced recent
admixture from ancestral groups originating in Africa and Europe. Zhu et
al. (2005) used a set of unrelated individuals from Nigeria to represent
the African ancestral population and used the European Americans in the
Family Blood Pressure Program to provide estimates of allele frequencies
for the European ancestors. They genotyped a common set of 269
microsatellite markers in the 3 groups at the same laboratory. The
distribution of marker location-specific African ancestry, based on
multipoint analysis, was shifted upward in hypertensive cases versus
normotensive controls, consistent with linkage to genes conferring
susceptibility. This shift was largely due to a small number of loci,
including 5 adjacent markers on chromosome 6q and 2 on chromosome 21q.
The most significant markers that were increased in hypertensive African
Americans in 3 different samples and that showed excess of African
ancestry among hypertensive cases compared with controls were GATA184A08
on chromosome 6q24 (lod score = 4.14) and D21S1437 on chromosome 21q21
(lod score = 4.34). Zhu et al. (2005) concluded that chromosome 6q24 and
chromosome 21q21 may contain genes influencing risk of hypertension in
African Americans.

In a large-scale admixture scan for genes contributing to hypertension
risk in 1,670 African Americans and 387 control individuals, Deo et al.
(2007) identified no candidate genes or linkage peaks that appeared to
contribute substantially to the differential risk between African and
European Americans. They did observe nominal association at the
chromosome 6q24 location (p = 0.16) identified by Zhu et al. (2005).
They noted that the study sample used by Zhu et al. (2005) with multiple
affected family members may explain the difference in the findings.

Chromosome 8p

Wu et al. (1996) studied the distribution of blood pressure in 48
Taiwanese families with noninsulin-dependent diabetes mellitus and
conducted quantitative sib-pair linkage analysis with candidate loci for
insulin resistance, lipid metabolism, and blood pressure control. They
obtained significant evidence for linkage of systolic blood pressure,
but not diastolic blood pressure, to a genetic region at or near the
lipoprotein lipase (238600) locus on 8p. Allelic variation around the
LPL gene locus was estimated to account for as much as 52 to 73% of the
total interindividual variation in systolic blood pressure levels.

Chromosome 11q24.1

Rutherford et al. (2007) identified a quantitative trait locus (QTL) on
chromosome 11q24.1 that influenced change of blood pressure measurements
over time in Mexican Americans of the San Antonio Family Heart Study.
Significant evidence of linkage was found for rate of change in systolic
blood pressure (lod = 4.15) and for rate of change in mean blood
pressure (lod = 3.94) near marker D11S4464. Rutherford et al. (2007)
presented results from fine mapping the chromosome 11 QTL with use of
SNP-associated analysis within candidate genes identified from a
bioinformatic search of the region and from whole genome transcriptional
expression data. The results showed that the use of longitudinal blood
pressure data to calculate the rate of change in blood pressure over
time provides more information than do the single-time measurements,
since they reveal physiologic trends in subjects that a single-time
measurement could never capture.

Chromosome 12q

Frossard and Lestringant (1995) carried out association studies at a
candidate locus, the pancreatic phospholipase A2 gene (PLA2A; 172410),
located on chromosome 12q. Positive associations were found between the
presence of a TaqI dimorphic site located in the first intron of this
gene and hypertension in 3 populations sampled: 2 from USA and 1 from
Germany. The results indicated that a QTL (quantitative trait locus)
implicated in determining an individual's genetic susceptibility to
hypertension may be present within up to 30 cM of the PLA2A gene.
Phospholipase A2 is a rate-limiting enzyme in eicosanoid production. It
is coupled to angiotensin II receptors and acts, upon activation by
increased intracellular calcium, to release esterified arachidonic acid
from membrane phospholipids.

Chromosome 14

Von Wowern et al. (2003) performed a 10-cM genomewide scan in
Scandinavian sib pairs (243 patients among 91 sibships) with early onset
primary hypertension. After fine mapping of the loci, significant
linkage was obtained on chromosome 14 (p = 0.0002 at 41 cM), nearest to
marker D14S288 (Z = 2.7).

Chromosome 18p11

Studies in hypertensive humans and rats, as well as in familial
orthostatic hypotensive syndrome (143850), suggested that chromosome 18
may have a role in hypertension. In a study using 12 microsatellite
markers spanning human chromosome 18 in 177 Australian Caucasian
hypertensive sib pairs, Rutherford et al. (2004) found that there was
significant excess allele sharing of the D18S61 marker. The adenylate
cyclase-activating polypeptide-1 gene (ADCYAP1; 102980) is involved in
vasodilation and maps to the same region (18p11) as the D18S59 marker.
Testing a microsatellite marker in the 3-prime untranslated region of
ADCYAP1 in age- and gender-matched hypertensive and normotensive
individuals showed possible association with hypertension.

Chromosome 21q21

As a complement to linkage and candidate gene association studies, Zhu
et al. (2005) carried out admixture mapping using genome scan
microsatellite markers among the African American participants in the
U.S. National Heart, Lung, and Blood Institute's Family Blood Pressure
Program. This population was assumed to have experienced recent
admixture from ancestral groups originating in Africa and Europe. Zhu et
al. (2005) used a set of unrelated individuals from Nigeria to represent
the African ancestral population and used the European Americans in the
Family Blood Pressure Program to provide estimates of allele frequencies
for the European ancestors. They genotyped a common set of 269
microsatellite markers in the 3 groups at the same laboratory. The
distribution of marker location-specific African ancestry, based on
multipoint analysis, was shifted upward in hypertensive cases versus
normotensive controls, consistent with linkage to genes conferring
susceptibility. This shift was largely due to a small number of loci,
including 5 adjacent markers on chromosome 6q and 2 on chromosome 21q.
The most significant markers that were increased in hypertensive African
Americans in 3 different samples and that showed excess of African
ancestry among hypertensive cases compared with controls were GATA184A08
on chromosome 6q24 (lod score = 4.14) and D21S1437 on chromosome 21q21
(lod score = 4.34). Zhu et al. (2005) concluded that chromosome 6q24 and
chromosome 21q21 may contain genes influencing risk of hypertension in
African Americans.

In a large-scale admixture scan for genes contributing to hypertension
risk in 1,670 African Americans and 387 control individuals, Deo et al.
(2007) identified no candidate genes or linkage peaks that appeared to
contribute substantially to the differential risk between African and
European Americans, including the chromosome 21q21 locus identified by
Zhu et al. (2005).

- Genomewide Linkage Studies

To search systematically for chromosomal regions containing genes that
regulate blood pressure, Xu et al. (1999) scanned the entire autosomal
genome using 367 polymorphic markers. The study population, selected
from a blood pressure screen of more than 200,000 Chinese adults,
comprised rare but highly efficient extreme sib pairs (207 discordant,
258 high concordant, and 99 low concordant) and all but 1 parent of
these sibs. By virtue of the sampling design, the number of sib pairs,
and the availability of genotyped parents, this study represented one of
the most powerful of its kind. Although no regions achieved a 5%
genomewide significance level, maximum lod scores were greater than 2.0
for regions of chromosomes 3, 11, 15, 16, and 17.

- Exclusion Linkage Studies

Jeunemaitre et al. (1992) could demonstrate no linkage between
hypertension and the angiotensin I-converting enzyme locus (ACE; 106180)
on chromosome 17. Wu et al. (1996) studied the distribution of blood
pressure in 48 Taiwanese families with noninsulin-dependent diabetes
mellitus and conducted quantitative sib-pair linkage analysis with
candidate loci for insulin resistance, lipid metabolism, and blood
pressure control. They found no evidence for linkage of the ACE gene on
chromosome 17, nor the angiotensinogen and renin loci on chromosome 1,
with either systolic or diastolic blood pressures.

MOLECULAR GENETICS

In a review, Garbers and Dubois (1999) identified a number of important
blood pressure regulatory genes, including their loci in the human,
mouse, and rat genomes. Phenotypes of gene deletions and overexpression
in mice were summarized, and a detailed discussion of selected gene
products was included.

ANIMAL MODEL

De Mendonca et al. (1980) found the same changes as those reported by
Garay and Meyer (1979) in 3 varieties of genetically transmitted
hypertension in the rat: an abnormally low ratio of Na+ to K+ net fluxes
in sodium-loading and potassium-depleted erythrocytes.

Kurtz and Morris (1985) found that recently weaned Dahl rats (Dahl et
al., 1962) already had a higher than normal blood pressure and greater
heart weight to body weight ratio than did normal rats. Thus, the
hypertension that develops with salt challenge is superimposed on an
already extant difference in blood pressure between strains. Rapp et al.
(1989) found that Dahl rats sensitive to hypertension with salt
administration had a different RFLP in the renin gene than did Dahl rats
resistant to hypertension. They found, furthermore, that when the
sensitive and the resistant rats were crossed, the renin RFLP
cosegregated with blood pressure in the F2 generation. One dose of the
'sensitive' renin allele was associated with an increment of blood
pressure approximately 10 mm Hg, and 2 doses increased blood pressure
approximately 20 mm Hg. Rapp et al. (1989) concluded that in the rat the
renin gene is, or is closely linked to, 1 of the genes regulating blood
pressure.

In a study of crosses between the stroke-prone spontaneously
hypertensive rat and the normotensive control strain, Hilbert et al.
(1991) localized 2 genes, BP/SP-1 and BP/SP-2, that contribute
significantly to blood pressure variation in the F-2 generation. The 2
genes were assigned to rat chromosomes 10 and X, respectively.
Comparison of the human and rat genetic maps indicated that the human
homolog of BP/SP-1 could reside on chromosome 17q in a region that also
contains the angiotensin I-converting enzyme gene. Since ACE1 encodes a
key enzyme of the renin-angiotensin system, it is a prime candidate gene
in primary hypertension. A rat microsatellite marker of the gene was
mapped to rat chromosome 10 within the region containing BP/SP-1. In
precisely the same cross prepared by the same investigators, Jacob et
al. (1991) likewise mapped a gene they called Bp1 to rat chromosome 10
and demonstrated close linkage to the rat gene for angiotensin
I-converting enzyme. They also identified significant, albeit weaker,
linkage to a locus, Bp2, on chromosome 18 of the rat. Phenylethanolamine
N-methyltransferase (PNMT; 171190), which catalyzes the synthesis of
epinephrine from norepinephrine, is encoded by a gene on human
chromosome 17 and rat chromosome 10 and is, therefore, also a candidate
gene for hypertension in the rat model.

Kreutz et al. (1995) reported further characterization of the BP/SP-1
locus, using a congenic strain of rats carrying a 6-cM chromosomal
fragment genotypically identical with the segment on chromosome 10 in
the stroke-prone spontaneously hypertensive rat (SHRSP) in whom the
BP/SP-1 locus was originally identified. This segment was 26 cM away
from the ACE locus. From breeding experiments they concluded that a QTL,
termed BP/SP-1a, lies within the SHRSP-congenic region and is linked to
basal blood pressure, whereas a second locus on chromosome 10, termed
BP/SP-1b, that maps closer to the ACE locus cosegregates predominantly
with blood pressure after exposure to excess dietary NaCl. Through the
study of inbred Dahl salt-sensitive rats, Gu et al. (1996) demonstrated
2 blood pressure QTLs on rat chromosome 1.

Benediktsson et al. (1993) found that rat placental 11-beta-OHSD
activity correlated positively with term fetal weight and negatively
with placental weight. Offspring of rats treated during pregnancy with
dexamethasone (which is not metabolized by 11-beta-OHSD) had lower birth
weights and higher blood pressure when adults than did offspring of
control rats.

Cicila et al. (1993) found a difference between Dahl salt-hypertension
sensitive (S) and resistant (R) strains of rats, namely, a polymorphism
of 11-beta hydroxylase (202010) that cosegregated with the capacity of
the adrenal to synthesize 18-hydroxy-11-deoxycorticosterone (18-OH-DOC).
They found that the R rat carries an 11-beta hydroxylase allele that is
associated with uniquely reduced capacity to synthesize 18-OH-DOC and
encodes an 11-beta-hydroxylase protein with 5 amino acid substitutions.
The gene for 11-beta-hydroxylase is located on rat chromosome 7. Dubay
et al. (1993) showed that in the Lyon hypertensive rat strain different
loci are involved in the regulation of steady-state (diastolic pressure)
and pulsatile (systolic minus diastolic, or pulse pressure) components
of blood pressure. Significant linkage was established between diastolic
blood pressure and a microsatellite marker of the renin gene on rat
chromosome 13, and between pulse pressure and the carboxypeptidase B
gene (114852) on rat chromosome 2. Deng et al. (1994) localized a blood
pressure QTL on rat chromosome 2 between 2 candidate loci. They
estimated that the particular QTL accounted for 9.2% of the total
variance and 26% of the genetic variance.

End-stage renal disease, coronary artery disease, and stroke are
complications of hypertension. Why some patients develop complications
is unclear, but susceptibility genes may be involved. To test this
notion, Brown et al. (1996) studied crosses involving the fawn-hooded
rat, an animal model of hypertension that develops chronic renal
failure. They were able to localize 2 genes, designated Rf1 and Rf2 by
them, which were responsible for about half of the genetic variation in
key indices of renal impairment. In addition, they localized another
gene, called Bpfh1, which was responsible for about 26% of the genetic
variation in blood pressure. Rf1 strongly affected the risk of renal
impairment, but had no significant effect on blood pressure. The results
showed that susceptibility to a complication of hypertension is under at
least partially independent genetic control from susceptibility to
hypertension itself.

Vincent et al. (1997) presented evidence that genetic factors may
influence the response to antihypertensive drugs. In a backcross
population derived from a cross of the Lyon hypertensive rat with Lyon
normotensive rat, they used microsatellite markers to identify a QTL on
rat chromosome 2 that specifically influences the systolic and diastolic
blood pressure responses to administration of a dihydropyridine calcium
antagonist. The locus accounted for 10.3% and 10.4% of the total
variances in the systolic and diastolic responses to the drug,
respectively. In marked contrast, the locus had no effect on either
basal blood pressure or on the responses to acute administration of
trimetaphan, a ganglionic blocking agent, or of losartan, an angiotensin
II subtype 1 receptor (106165) antagonist.

Churchill et al. (1997) tested the role of genetic factors in
determining hypertension-induced renal damage by developing a new
experimental animal model. Two genetically distinct yet histocompatible
kidneys were chronically and simultaneously exposed to the same blood
pressure profile and metabolic environment in the same host. Kidneys
from normotensive Brown Norway rats were transplanted into unilaterally
nephrectomized spontaneously hypertensive rats that carried the major
histocompatibility complex of the Brown Norway strain. After 25 days of
severe hypertension induced by deoxycorticosterone acetate (DOCA) and
salt, Brown Norway donor kidneys, but not spontaneously hypertensive rat
kidneys, developed proteinuria, impaired glomerular filtration rate, and
extensive vascular and glomerular injury. Control experiments showed
that strain differences in renal damage were not related to
transplantation-induced renal injury, immunologic rejection, or
preexisting strain differences in blood pressure. These studies
demonstrated that differences in susceptibility to hypertension-induced
renal damage are genetic in these rat strains and established the
feasibility of using organ-specific genome transplants to map genes
expressed in the kidney. Brown Norway rats showed no blood pressure
response to DOCA-salt, showing additional genetic differences in
hypertension.

Tanaka et al. (1997) found that in SHRSP rats on a normal NaCl diet,
supplementing dietary potassium with KCl exacerbated hypertension,
whereas supplementing either K-bicarbonate or K-citrate (KB/C)
attenuated hypertension. Supplemental KCl but not KB/C induced stroke in
all and only those rats in the highest quartiles of both blood pressure
and plasma renin activity. Plasma renin activity was higher with KCl
than with KB/C. These observations were interpreted as showing that the
severity of hypertension and frequency of stroke in SHRSP rats were
selectively Cl(-)-sensitive and Cl(-)-determined.

HISTORY

Lifton et al. (1991) excluded APNH (107310) as a candidate gene for
susceptibility to essential hypertension.

*FIELD* SA
Acheson and Fowler (1967); Anonymous (1983); Garay et al. (1980);
Garay and Meyer (1981); Hasstedt et al. (1988); Ibsen et al. (1982);
Parker (1980); Trippodo and Frohlich (1981); Woods et al. (1981)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Multifactorial

CARDIOVASCULAR:
[Vascular];
Elevated systolic blood pressure;
Elevated diastolic blood pressure;
Elevated mean arterial pressure

MISCELLANEOUS:
Multiple genes influence susceptibility to hypertension. Candidate
genes include angiotensinogen (AGT, 106150), angiotensin receptor-1
(AGTR1, 106165), and beta-3 subunit of guanine nucleotide-binding
protein (GNB3, 139130). Susceptibility loci include HYT1 (603918)
and HYT2 (604329).

*FIELD* CN
Ada Hamosh - reviewed: 5/15/2000
Kelly A. Przylepa - revised: 3/27/2000

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

*FIELD* ED
joanna: 05/16/2000
joanna: 5/15/2000
kayiaros: 3/27/2000

*FIELD* CN
Marla J. F. O'Neill - updated: 04/01/2013
Marla J. F. O'Neill - updated: 7/7/2009
Victor A. McKusick - updated: 10/8/2007
Marla J. F. O'Neill - updated: 5/10/2007
George E. Tiller - updated: 4/5/2007
Victor A. McKusick - updated: 1/18/2007
Victor A. McKusick - updated: 7/10/2006
Marla J. F. O'Neill - updated: 9/2/2005
George E. Tiller - updated: 6/6/2005
Ada Hamosh - updated: 3/14/2005
George E. Tiller - updated: 6/17/2004
Victor A. McKusick - updated: 4/14/2004
Victor A. McKusick - updated: 10/30/2002
Victor A. McKusick - updated: 12/27/2001
George E. Tiller - updated: 10/25/2000
Victor A. McKusick - updated: 10/26/1999
Wilson H. Y. Lo - updated: 7/14/1999
Victor A. McKusick - updated: 6/4/1999
Victor A. McKusick - updated: 5/27/1999
Victor A. McKusick - updated: 2/15/1999
Victor A. McKusick - updated: 12/30/1997
Victor A. McKusick - updated: 11/20/1997
Ada Hamosh - updated: 10/21/1997
Michael J. Wright - updated: 9/24/1997
Victor A. McKusick - updated: 8/12/1997
Mark H. Paalman - updated: 5/14/1996

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

*FIELD* ED
carol: 04/01/2013
terry: 4/1/2013
carol: 8/8/2012
carol: 7/7/2009
terry: 6/3/2009
carol: 6/3/2009
carol: 11/26/2008
carol: 6/4/2008
carol: 5/16/2008
alopez: 10/8/2007
carol: 5/10/2007
alopez: 4/20/2007
alopez: 4/17/2007
terry: 4/5/2007
alopez: 1/19/2007
terry: 1/18/2007
carol: 12/13/2006
terry: 8/25/2006
terry: 8/24/2006
alopez: 7/18/2006
terry: 7/10/2006
wwang: 9/2/2005
wwang: 7/15/2005
alopez: 6/6/2005
carol: 5/25/2005
tkritzer: 3/16/2005
terry: 3/14/2005
alopez: 1/6/2005
alopez: 1/5/2005
carol: 11/16/2004
tkritzer: 7/14/2004
alopez: 6/17/2004
alopez: 4/16/2004
terry: 4/14/2004
cwells: 11/7/2003
carol: 2/27/2003
carol: 12/2/2002
mgross: 10/31/2002
terry: 10/30/2002
alopez: 1/11/2002
carol: 1/11/2002
cwells: 1/3/2002
terry: 12/27/2001
mcapotos: 11/1/2000
mcapotos: 10/25/2000
mgross: 1/10/2000
mgross: 12/20/1999
mgross: 12/16/1999
terry: 12/9/1999
carol: 11/3/1999
carol: 10/27/1999
terry: 10/26/1999
carol: 10/18/1999
carol: 7/23/1999
kayiaros: 7/14/1999
mgross: 6/24/1999
mgross: 6/17/1999
terry: 6/4/1999
mgross: 6/3/1999
terry: 5/27/1999
alopez: 3/3/1999
terry: 2/15/1999
carol: 10/12/1998
terry: 10/6/1998
terry: 5/29/1998
alopez: 1/7/1998
terry: 1/6/1998
dholmes: 12/9/1997
alopez: 12/8/1997
alopez: 12/3/1997
alopez: 11/26/1997
terry: 11/21/1997
terry: 11/20/1997
joanna: 11/19/1997
jenny: 11/12/1997
terry: 11/10/1997
alopez: 11/7/1997
alopez: 11/5/1997
mark: 8/15/1997
terry: 8/12/1997
terry: 6/3/1996
terry: 5/29/1996
mark: 5/15/1996
terry: 5/14/1996
mark: 5/10/1996
terry: 5/10/1996
mark: 3/27/1996
mark: 3/21/1996
terry: 3/13/1996
mark: 1/4/1996
terry: 1/3/1996
mark: 9/28/1995
pfoster: 4/7/1995
terry: 8/26/1994
jason: 6/13/1994
carol: 5/24/1994
mimadm: 4/13/1994

MIM 267430
*RECORD*
*FIELD* NO
267430
*FIELD* TI
#267430 RENAL TUBULAR DYSGENESIS; RTD
;;PRIMITIVE RENAL TUBULE SYNDROME
RENAL TUBULAR DYSGENESIS WITH CHOANAL ATRESIA AND ATHELIA, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because renal tubular
dysgenesis is caused by homozygous or compound heterozygous mutation in
genes encoding components of the renin-angiotensin system: renin
(179820) on chromosome 1q32, angiotensinogen (106150) on chromosome
1q42, angiotensin-converting enzyme (106180) on chromosome 17q23, or
angiotensin II receptor type 1 (106165) on chromosome 3q24.

DESCRIPTION

Autosomal recessive renal tubular dysgenesis is a severe disorder of
renal tubular development characterized by persistent fetal anuria and
perinatal death, probably due to pulmonary hypoplasia from early-onset
oligohydramnios (the Potter phenotype) (Gribouval et al., 2005). Absence
or paucity of differentiated proximal tubules is the histopathologic
hallmark of the disorder and may be associated with skull ossification
defects.

CLINICAL FEATURES

Allanson et al. (1983) described 2 stillborn females born consecutively
of a nonconsanguineous Chinese couple. Both had the Potter syndrome
resulting from oligohydramnios and showed a seemingly unique histologic
change in the kidneys. Normal proximal convoluted tubules were absent
and all tubules appeared abnormally developed, primitive and reminiscent
of collecting tubules. The father had suffered from 'minimal change'
glomerulonephritis. Swinford et al. (1986) described a second
nonconsanguineous family of northern European and American descent in
which 2 males and 1 female died with oligohydramnios sequence and
pulmonary hypoplasia. The renal tissue in these children demonstrated
abnormally developed, primitive renal tubules and interstitial fibrous
connective tissue.

Schwartz et al. (1986) described male and female sibs with congenital
renal tubular immaturity.

MacMahon et al. (1990) reported a typical case in an infant born of
unrelated parents and reviewed 12 previous cases distributed in 5
families.

Russo et al. (1991) reported an infant with this disorder who survived
for 15 days after birth. The infant also had acrocephalosyndactyly of
the Saethre-Chotzen type (101400), which was present in other members of
the family.

Allanson et al. (1992) reported an additional 9 cases from one pediatric
center. Early prenatal diagnosis may be difficult because amniotic fluid
volumes have been shown to be normal in affected pregnancies before 22
weeks' gestation. Late second trimester sonographic demonstration of
oligohydramnios, with structurally normal kidneys, should suggest the
diagnosis and the need for detailed postmortem pathologic examination
for this disorder, which may not be as rare as was previously thought.

Ariel et al. (1995) described a family in which consanguineous
Palestinian Muslim Arab parents had 3 affected children. Microdissection
of the nephrons in a male infant who died 30 hours after birth showed
marked hypoplasia of all segments of the nephron, from the glomerulus to
the collecting tubule. The authors suggested that hypoplasia of the
distal parts of nephron, as well as the proximal convoluted tubule, is
characteristic for this disorder.

McFadden et al. (1997) reported 2 cases of renal tubular dysgenesis,
both of whom had calvarial hypoplasia. They noted that 6 of the 24 cases
reported by Allanson et al. (1992) had associated microcephaly,
underdeveloped cranial bones, or widely patent fontanels, and that a
number of other reported cases had skull abnormalities. McFadden et al.
(1997) suggested that skull abnormalities are a common component of the
inherited form of renal tubular dysgenesis, as they are in the acquired
form of renal tubular dysgenesis associated with maternal use of
angiotensin-converting enzyme (ACE; 106180) inhibitors. McFadden et al.
(1997) concluded that skull abnormalities may be important in suggesting
the diagnosis of renal tubular dysgenesis.

Uematsu et al. (2006) reported a Japanese female infant with renal
tubular dysgenesis. The patient was born at 35 weeks gestation with
Potter syndrome, hypoplastic lungs, and severe hypotension. Treatment
with fresh frozen plasma and peritoneal dialysis resulted in clinical
improvement and she had spontaneous urination at day 29. Endocrine
studies showed a discrepancy between low plasma renin activity and high
active renin concentrations, suggesting a negative feedback loop
response in the renin-angiotensin system. At age 18 months, she had no
obvious motor or mental retardation. An older brother with similar
features had died a few days after birth.

- Renal Tubular Dysgenesis with Choanal Atresia and Athelia

Hisama et al. (1998) reported a lethal syndrome in 3 brothers which was
characterized particularly by renal tubular dysgenesis and absent
nipples (athelia). All 3 infants died neonatally and each had other
malformations including preauricular pits and a preauricular tag,
branchial clefts, choanal atresia, pulmonary lobation anomaly,
ventricular septal defect, type IIB interrupted aortic arch, absent
gallbladder, absent thymus, parathyroid gland, accessory spleen,
imperforate anus, clinodactyly, and broad digits and small nails. One
had a marker chromosome which appeared to be mainly Y heterochromatin
and was probably unrelated to the syndrome because it was absent in the
other 2 patients. X-linked recessive inheritance was possible; however,
there were 4 healthy maternal uncles. Autosomal dominant inheritance
with gonadal mosaicism also could not be excluded. Furthermore, a subtle
chromosomal abnormality leading to contiguous gene effects could not be
ruled out.

Horvath and Armstrong (2007) described a female infant, born to a
nonconsanguineous couple who had 2 previous miscarriages, who appeared
to share a syndrome with the 3 brothers reported by Hisama et al.
(1998). Her renal function was initially impaired, but improved over the
first weeks of life, although there was persistent renal magnesium
wasting. Her craniofacial appearance with infraorbital creases and
low-set, dysplastic ears was similar to that described by Hisama et al.
(1998); she also had choanal atresia, gingival cysts, a preauricular
pit, athelia, right aortic arch with a vascular ring, broad digits with
small nails, impaired glucose homeostasis, hypoadrenalism, neurologic
impairment, and brain calcifications and periventricular leukomalacia on
CT scan. She died at 13 weeks due to progressive central respiratory
failure. There was a family history of neck cysts, renal failure, and
adult-onset nasal passage problems. Horvath and Armstrong (2007)
considered the 4 salient features of this apparent syndrome to be
choanal atresia/stenosis, athelia, renal tubular dysfunction, and family
and/or personal history of neck cysts or branchial clefts.

MOLECULAR GENETICS

Gribouval et al. (2005) studied 11 individuals with renal tubular
dysgenesis (RTD) belonging to 9 families and found that they had
homozygous or compound heterozygous mutations in the genes encoding
renin (REN; 179820.0002), angiotensinogen (AGT; 106150.0003),
angiotensin-converting enzyme (ACE; 106180.0003), or angiotensin II
receptor type 1 (AGTR1; 106165.0003). They proposed that renal lesions
and early anuria result from chronic low perfusion pressure of the fetal
kidney, a consequence of renin-angiotensin system inactivity. This
appeared to be the first identification of a renal mendelian disorder
linked to genetic defects in the renin-angiotensin system, highlighting
the crucial role of the renin-angiotensin system in human kidney
development. Hypoperfusion of the fetal kidneys had been suggested as
the mechanism of RTD by findings in the twin-twin transfusion syndrome
in monochorionic twin gestations (in which the donor fetus may develop
RTD), major cardiac malformations, and severe liver diseases. RTD with
large fontanels has also been observed in fetuses exposed in utero to
ACE inhibitors or angiotensin II receptor antagonists. Severe fetal
hypotension may also account for hypocalvaria, another feature of RTD of
both the primary and secondary types. In contrast with endochondral
bones, unaffected in RTD, persistent low blood pressure may affect skull
membrane bone, which is highly vascular and requires high oxygen tension
for normal growth and ossification (Barr and Cohen, 1991). Wide
fontanels were described in several of the cases of renal tubular
dysgenesis studied by Gribouval et al. (2005).

In a Japanese infant with renal tubular dysgenesis, Uematsu et al.
(2006) identified compound heterozygosity for 2 mutations in the AGT
gene (106150.0004 and 106150.0005).

Gribouval et al. (2012) reviewed 54 distinct mutations identified in 48
unrelated families with renal tubular dysgenesis, some of whom had
previously been reported. Mutations in the ACE gene were the most
common, found in 64.4% of families. Mutations in the REN gene were found
in 20% of families, whereas AGT mutations were found in only 4 families,
and AGTR1 mutations in 3 (8.3%). There were no genotype/phenotype
correlations. The findings indicated that the disorder is due to defects
affecting the common RAS pathway, regardless of the specific gene
involved. Inactivation of the RAS pathway results in low systemic blood
pressure and renal blood flow during fetal life, precluding normal
development of the renal tubules.

*FIELD* RF
1. Allanson, J. E.; Hunter, A. G. W.; Mettler, G. S.; Jimenez, C.
: Renal tubular dysgenesis: a not uncommon autosomal recessive syndrome:
a review. Am. J. Med. Genet. 43: 811-814, 1992.

2. Allanson, J. E.; Pantzar, J. T.; MacLeod, P. M.: Possible new
autosomal recessive syndrome with unusual renal histopathological
changes. Am. J. Med. Genet. 16: 57-60, 1983.

3. Ariel, I.; Wells, T. R.; Landing, B. H.; Sagi, M.; Bar-Oz, B.;
Ron, N.; Rosenmann, E.: Familial renal tubular dysgenesis: a disorder
not isolated to proximal convoluted tubules. Pediat. Path. Lab. Med. 15:
915-922, 1995.

4. Barr, M., Jr.; Cohen, M. M., Jr.: ACE inhibitor fetopathy and
hypocalvaria: the kidney-skull connection. Teratology 44: 485-495,
1991.

5. Gribouval, O.; Gonzales, M.; Neuhaus, T.; Aziza, J.; Bieth, E.;
Laurent, N.; Bouton, J. M.; Feuillet, F.; Makni, S.; Ben Amar, H.;
Laube, G.; Delezoide, A.-L.; Bouvier, R.; Dijoud, F.; Ollagnon-Roman,
E.; Roume, J.; Joubert, M.; Antignac, C.; Gubler, M. C.: Mutations
in genes in the renin-angiotensin system are associated with autosomal
recessive renal tubular dysgenesis. Nature Genet. 37: 964-968, 2005.

6. Gribouval, O.; Moriniere, V.; Pawtowski, A.; Arrondel, C.; Sallinen,
S.-L.; Saloranta, C.; Clericuzio, C.; Viot, G.; Tantau, J.; Blesson,
S.; Cloarec, S.; Machet, M. C.; and 43 others: Spectrum of mutations
in the renin-angiotensin system genes in autosomal recessive renal
tubular dysgenesis. Hum. Mutat. 33: 316-326, 2012.

7. Hisama, F. M.; Reyes-Mugica, M.; Wargowski, D. S.; Thompson, K.
J.; Mahoney, M. J.: Renal tubular dysgenesis, absent nipples, and
multiple malformations in three brothers: a new, lethal syndrome. Am.
J. Med. Genet. 80: 335-342, 1998.

8. Horvath, G. A.; Armstrong, L.: Report of a fourth individual with
a lethal syndrome of choanal atresia, athelia, evidence of renal tubulopathy,
and family history of neck cysts. Am. J. Hum. Genet. 143A: 1231-1235,
2007.

9. MacMahon, P.; Blackie, R. A. S.; House, M. J.; Risdon, R. A.; Crawfurd,
M. d'A.: A further family with congenital renal proximal tubular
dysgenesis. J. Med. Genet. 27: 395-398, 1990.

10. McFadden, D. E.; Pantzar, J. T.; Van Allen, M. I.; Langlois, S.
: Renal tubular dysgenesis with calvarial hypoplasia: report of two
additional cases and review. J. Med. Genet. 34: 846-848, 1997.

11. Russo, R.; D'Armiento, M.; Vecchione, R.: Renal tubular dysgenesis
and very large cranial fontanels in a family with acrocephalosyndactyly
S.C. type. Am. J. Med. Genet. 39: 482-485, 1991.

12. Schwartz, B. R.; Lage, J. M.; Pober, B. R.; Driscoll, S. G.:
Isolated congenital renal tubular immaturity in siblings. Hum. Path. 17:
1259-1263, 1986.

13. Swinford, A. E.; Bernstein, J.; Higgins, J. V.; Pradhan, S.:
Confirmation of an autosomal recessive renal syndrome characterized
by primitive renal tubules. (Abstract) Am. J. Hum. Genet. 39: A83
only, 1986.

14. Uematsu, M.; Sakamoto, O.; Nishio, T.; Ohura, T.; Matsuda, T.;
Inagaki, T.; Abe, T.; Okamura, K.; Kondo, Y.; Tsuchiya, S.: A case
surviving for over a year of renal tubular dysgenesis with compound
heterozygous angiotensinogen gene mutations. Am. J. Med. Genet. 140A:
2355-2360, 2006.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Potter facies

CARDIOVASCULAR:
[Vascular];
Hypotension, severe

RESPIRATORY:
[Lung];
Pulmonary hypoplasia secondary to oligohydramnios;
Neonatal respiratory failure due to pulmonary hypoplasia

GENITOURINARY:
[Kidneys];
Renal tubular dysgenesis;
Kidney biopsy shows absence of differentiated proximal tubules;
Primitive renal tubules may exist;
Thickening of renal arterial walls;
Anuria

SKELETAL:
[Skull];
Hypoplasia of the membranous bones of the skull;
Underdeveloped membranous cranial bones;
Calvaria hypoplasia;
Wide cranial sutures;
Large fontanelles

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios, severe;
Fetal anuria

MISCELLANEOUS:
Affected infants often die in utero or in the postnatal period

MOLECULAR BASIS:
Caused by mutation in the renin gene (REN, 179820.0002);
Caused by mutation in the angiotensinogen gene (AGT, 106150.0003);
Caused by mutation in the angiotensin-converting enzyme gene (ACE,
106180.0003);
Caused by mutation in the angiotensin II receptor type 1 gene (AGTR1,
106165.0003)

*FIELD* CN
Cassandra L. Kniffin - revised: 7/19/2006

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

*FIELD* ED
joanna: 05/30/2008
ckniffin: 12/21/2006
ckniffin: 7/19/2006
alopez: 9/27/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2013
Marla J. F. O'Neill - updated: 2/1/2008
Cassandra L. Kniffin - updated: 12/21/2006
Victor A. McKusick - updated: 9/27/2005
Victor A. McKusick - updated: 12/30/1998
Michael J. Wright - updated: 6/5/1998
Iosif W. Lurie - updated: 1/8/1997

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

*FIELD* ED
carol: 05/02/2013
ckniffin: 5/1/2013
terry: 3/20/2012
wwang: 2/3/2010
wwang: 2/5/2008
terry: 2/1/2008
wwang: 1/22/2007
ckniffin: 12/21/2006
terry: 12/14/2005
alopez: 9/28/2005
terry: 9/27/2005
alopez: 7/14/2005
tkritzer: 1/20/2005
mgross: 3/17/2004
carol: 1/6/1999
terry: 12/30/1998
alopez: 6/17/1998
terry: 6/5/1998
terry: 3/6/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
mimadm: 3/12/1994
carol: 8/24/1992
supermim: 3/17/1992
carol: 6/25/1991
carol: 7/3/1990
supermim: 3/20/1990