Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy
Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR a...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2000-07, Vol.289 (5476), p.119-123 |
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| creator | Geller, David S. Farhi, Anita Pinkerton, Nikki Fradley, Michael Moritz, Michael Spitzer, Adrian Meinke, Gretchen Francis T. F. Tsai Sigler, Paul B. Lifton, Richard P. |
| description | Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation. |
| doi_str_mv | 10.1126/science.289.5476.119 |
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F. Tsai ; Sigler, Paul B. ; Lifton, Richard P.</creator><creatorcontrib>Geller, David S. ; Farhi, Anita ; Pinkerton, Nikki ; Fradley, Michael ; Moritz, Michael ; Spitzer, Adrian ; Meinke, Gretchen ; Francis T. F. Tsai ; Sigler, Paul B. ; Lifton, Richard P.</creatorcontrib><description>Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.289.5476.119</identifier><identifier>PMID: 10884226</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Society for the Advancement of Science</publisher><subject>Adolescent ; Aldosterone - metabolism ; Amino Acid Sequence ; Amino Acid Substitution ; Amino acids ; Base Sequence ; Binding, Competitive ; Biological and medical sciences ; Blood pressure ; Causes of ; COS cells ; Dimerization ; Diseases of mother, fetus and pregnancy ; Female ; Genetic mutation ; Gestational hypertension ; Gynecology. Andrology. Obstetrics ; Heterozygote ; Humans ; Hypertension ; Hypertension - etiology ; Hypertension - genetics ; Hypertension - metabolism ; Hypertension in pregnancy ; Male ; Medical research ; Medical sciences ; mineralcorticoid receptors ; Models, Molecular ; Molecular Sequence Data ; Mutation ; nuclear homrmone receptors ; Nuclear receptors ; Pedigree ; Plasmids ; Point Mutation ; Preeclampsia ; Pregnancy ; Pregnancy Complications, Cardiovascular - etiology ; Pregnancy Complications, Cardiovascular - metabolism ; Pregnancy. Fetus. Placenta ; Progesterone - metabolism ; Protein Conformation ; Protein Structure, Secondary ; Receptors ; Receptors, Mineralocorticoid - chemistry ; Receptors, Mineralocorticoid - genetics ; Receptors, Mineralocorticoid - metabolism ; Receptors, Steroid - chemistry ; Receptors, Steroid - metabolism ; Steroids ; Steroids - metabolism</subject><ispartof>Science (American Association for the Advancement of Science), 2000-07, Vol.289 (5476), p.119-123</ispartof><rights>Copyright 2000 American Association for the Advancement of Science</rights><rights>2000 INIST-CNRS</rights><rights>COPYRIGHT 2000 American Association for the Advancement of Science</rights><rights>COPYRIGHT 2000 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Jul 7, 2000</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c783t-35e43b94f68519479c47732a5e920121481252e96b74f0775077c599fb565d9c3</citedby><cites>FETCH-LOGICAL-c783t-35e43b94f68519479c47732a5e920121481252e96b74f0775077c599fb565d9c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3077478$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3077478$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1460158$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10884226$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geller, David S.</creatorcontrib><creatorcontrib>Farhi, Anita</creatorcontrib><creatorcontrib>Pinkerton, Nikki</creatorcontrib><creatorcontrib>Fradley, Michael</creatorcontrib><creatorcontrib>Moritz, Michael</creatorcontrib><creatorcontrib>Spitzer, Adrian</creatorcontrib><creatorcontrib>Meinke, Gretchen</creatorcontrib><creatorcontrib>Francis T. F. Tsai</creatorcontrib><creatorcontrib>Sigler, Paul B.</creatorcontrib><creatorcontrib>Lifton, Richard P.</creatorcontrib><title>Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.</description><subject>Adolescent</subject><subject>Aldosterone - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Amino acids</subject><subject>Base Sequence</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Blood pressure</subject><subject>Causes of</subject><subject>COS cells</subject><subject>Dimerization</subject><subject>Diseases of mother, fetus and pregnancy</subject><subject>Female</subject><subject>Genetic mutation</subject><subject>Gestational hypertension</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension - etiology</subject><subject>Hypertension - genetics</subject><subject>Hypertension - metabolism</subject><subject>Hypertension in pregnancy</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>mineralcorticoid receptors</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>nuclear homrmone receptors</subject><subject>Nuclear receptors</subject><subject>Pedigree</subject><subject>Plasmids</subject><subject>Point Mutation</subject><subject>Preeclampsia</subject><subject>Pregnancy</subject><subject>Pregnancy Complications, Cardiovascular - etiology</subject><subject>Pregnancy Complications, Cardiovascular - metabolism</subject><subject>Pregnancy. Fetus. Placenta</subject><subject>Progesterone - metabolism</subject><subject>Protein Conformation</subject><subject>Protein Structure, Secondary</subject><subject>Receptors</subject><subject>Receptors, Mineralocorticoid - chemistry</subject><subject>Receptors, Mineralocorticoid - genetics</subject><subject>Receptors, Mineralocorticoid - metabolism</subject><subject>Receptors, Steroid - chemistry</subject><subject>Receptors, Steroid - metabolism</subject><subject>Steroids</subject><subject>Steroids - metabolism</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0-2L0zAYAPAiijdP_4NDihzqh-tM0rx-nOPcHeyc-PqxpNnTktGlM2nl9t-b0aFOho4SSp_8kpI8z5MkFxiNMSb8TTAWnIExkWrMqOAxqh4kI4wUyxRB-cNkhFDOM4kEO0uehLBCKM6p_HFyhpGUlBA-Sr5NTGd_6M66Or2zDrxuWtP6zprWLtOPYGDTtT6967toWpdal95sN-A7cGH3fX2vDfhSd7BMy236wUPttDPbp8mjSjcBnu3f58mXd9efpzfZfDG7nU7mmREy77KcAc1LRSsuGVZUKEOFyIlmEI-ACaYSE0ZA8VLQCgnB4jBMqapknC2Vyc-TV8O-G99-7yF0xdoGA02jHbR9KATNOeNciihf_ltiQiSS9L8QC8aI5CzCF3_BVdt7F49bEJwzKTmSEV0NqNYNFNZVbee1qWG4ageVjeEJzzmijO9-nh3h8VnCOubkiH994CPp4L6rdR9Ccfvp_cl08fVk-nZ2KpWz-QG9OkZN2zRQQxHrYro44HTgxrcheKiKjbdr7bcFRsWuBYp9CxSxBYpdC8Soisue77PSl2tY_rFoqPkILvdAB6Obysd6teG3oxxhtkvcxcBWIXbAr-k8ViCNtfsTg2YS9A</recordid><startdate>20000707</startdate><enddate>20000707</enddate><creator>Geller, David S.</creator><creator>Farhi, Anita</creator><creator>Pinkerton, Nikki</creator><creator>Fradley, Michael</creator><creator>Moritz, Michael</creator><creator>Spitzer, Adrian</creator><creator>Meinke, Gretchen</creator><creator>Francis T. 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Obstetrics</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Hypertension - etiology</topic><topic>Hypertension - genetics</topic><topic>Hypertension - metabolism</topic><topic>Hypertension in pregnancy</topic><topic>Male</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>mineralcorticoid receptors</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>nuclear homrmone receptors</topic><topic>Nuclear receptors</topic><topic>Pedigree</topic><topic>Plasmids</topic><topic>Point Mutation</topic><topic>Preeclampsia</topic><topic>Pregnancy</topic><topic>Pregnancy Complications, Cardiovascular - etiology</topic><topic>Pregnancy Complications, Cardiovascular - metabolism</topic><topic>Pregnancy. Fetus. Placenta</topic><topic>Progesterone - metabolism</topic><topic>Protein Conformation</topic><topic>Protein Structure, Secondary</topic><topic>Receptors</topic><topic>Receptors, Mineralocorticoid - chemistry</topic><topic>Receptors, Mineralocorticoid - genetics</topic><topic>Receptors, Mineralocorticoid - metabolism</topic><topic>Receptors, Steroid - chemistry</topic><topic>Receptors, Steroid - metabolism</topic><topic>Steroids</topic><topic>Steroids - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geller, David S.</creatorcontrib><creatorcontrib>Farhi, Anita</creatorcontrib><creatorcontrib>Pinkerton, Nikki</creatorcontrib><creatorcontrib>Fradley, Michael</creatorcontrib><creatorcontrib>Moritz, Michael</creatorcontrib><creatorcontrib>Spitzer, Adrian</creatorcontrib><creatorcontrib>Meinke, Gretchen</creatorcontrib><creatorcontrib>Francis T. F. 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F. Tsai</au><au>Sigler, Paul B.</au><au>Lifton, Richard P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2000-07-07</date><risdate>2000</risdate><volume>289</volume><issue>5476</issue><spage>119</spage><epage>123</epage><pages>119-123</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>10884226</pmid><doi>10.1126/science.289.5476.119</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2000-07, Vol.289 (5476), p.119-123 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743656687 |
| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Adolescent Aldosterone - metabolism Amino Acid Sequence Amino Acid Substitution Amino acids Base Sequence Binding, Competitive Biological and medical sciences Blood pressure Causes of COS cells Dimerization Diseases of mother, fetus and pregnancy Female Genetic mutation Gestational hypertension Gynecology. Andrology. Obstetrics Heterozygote Humans Hypertension Hypertension - etiology Hypertension - genetics Hypertension - metabolism Hypertension in pregnancy Male Medical research Medical sciences mineralcorticoid receptors Models, Molecular Molecular Sequence Data Mutation nuclear homrmone receptors Nuclear receptors Pedigree Plasmids Point Mutation Preeclampsia Pregnancy Pregnancy Complications, Cardiovascular - etiology Pregnancy Complications, Cardiovascular - metabolism Pregnancy. Fetus. Placenta Progesterone - metabolism Protein Conformation Protein Structure, Secondary Receptors Receptors, Mineralocorticoid - chemistry Receptors, Mineralocorticoid - genetics Receptors, Mineralocorticoid - metabolism Receptors, Steroid - chemistry Receptors, Steroid - metabolism Steroids Steroids - metabolism |
| title | Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T23%3A01%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Activating%20Mineralocorticoid%20Receptor%20Mutation%20in%20Hypertension%20Exacerbated%20by%20Pregnancy&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Geller,%20David%20S.&rft.date=2000-07-07&rft.volume=289&rft.issue=5476&rft.spage=119&rft.epage=123&rft.pages=119-123&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.289.5476.119&rft_dat=%3Cgale_proqu%3EA63604564%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213588608&rft_id=info:pmid/10884226&rft_galeid=A63604564&rft_jstor_id=3077478&rfr_iscdi=true |