Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene
ABSTRACT—Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in...
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| Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2003-08, Vol.42 (2), p.123-129 |
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| container_title | Hypertension (Dallas, Tex. 1979) |
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| creator | Lavery, Gareth G Ronconi, Vanessa Draper, Nicole Rabbitt, Elizabeth H Lyons, Val Chapman, Karen E Walker, Elizabeth A McTernan, Claire L Giacchetti, Gilberta Mantero, Franco Seckl, Jonathan R Edwards, Christopher R.W Connell, John M.C Hewison, Martin Stewart, Paul M |
| description | ABSTRACT—Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all |
| doi_str_mv | 10.1161/01.HYP.0000083340.57063.35 |
| format | Article |
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Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from “essential” hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the HSD11B2 locus can have on blood pressure in later life.</description><identifier>ISSN: 0194-911X</identifier><identifier>EISSN: 1524-4563</identifier><identifier>DOI: 10.1161/01.HYP.0000083340.57063.35</identifier><identifier>PMID: 12860834</identifier><identifier>CODEN: HPRTDN</identifier><language>eng</language><publisher>Philadelphia, PA: American Heart Association, Inc</publisher><subject>11-beta-Hydroxysteroid Dehydrogenase Type 2 ; Adolescent ; Adult ; Arterial hypertension. Arterial hypotension ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cell Line ; Clinical manifestations. Epidemiology. Investigative techniques. Etiology ; DNA, Complementary - metabolism ; Female ; Gene Expression ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Hydroxysteroid Dehydrogenases - genetics ; Hydroxysteroid Dehydrogenases - metabolism ; Hypertension - diagnosis ; Hypertension - genetics ; Hypokalemia - diagnosis ; Male ; Medical sciences ; Mineralocorticoids - metabolism ; Mutation ; Pedigree ; Phenotype</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2003-08, Vol.42 (2), p.123-129</ispartof><rights>2003 American Heart Association, Inc.</rights><rights>2004 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. 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Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from “essential” hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the HSD11B2 locus can have on blood pressure in later life.</description><subject>11-beta-Hydroxysteroid Dehydrogenase Type 2</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Arterial hypertension. Arterial hypotension</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cell Line</subject><subject>Clinical manifestations. Epidemiology. Investigative techniques. Etiology</subject><subject>DNA, Complementary - metabolism</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genetic Predisposition to Disease</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Hydroxysteroid Dehydrogenases - genetics</subject><subject>Hydroxysteroid Dehydrogenases - metabolism</subject><subject>Hypertension - diagnosis</subject><subject>Hypertension - genetics</subject><subject>Hypokalemia - diagnosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mineralocorticoids - metabolism</subject><subject>Mutation</subject><subject>Pedigree</subject><subject>Phenotype</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkVtvEzEQRi0EoqHwF5BVCd42eHzZC29taBuklCIBEjxZXu8s2bJZL7a3Jfx6nCZSJPwysnVm5pMPIWfA5gA5vGMwX_74PGe7Uwoh2VwVLBdzoZ6QGSguM6ly8ZTMGFQyqwC-n5AXIdwxBlLK4jk5AV7mqVXOyLgyEbPbIWCk5-NoPA6R3nQDetM763zsrOsaevnHYgh0YaaADa239JO7x54u3GZ009DQJUb07u_2p5sCvZmiiZ0bAu0GGtdIl18-AFxweo0DviTPWtMHfHWop-Tb1eXXxTJb3V5_XJyvMqtExTMhayjbihe2FbYyNW8rwduGi0KYoqgbbhlWuS1RNXVpRMMaBjaBpmC1akGJU_J2P3f07veEIepNFyz2vRkwhdSFUJWSBSTw7D_wzk1-SNk0Z4qXwHOWoPd7yHoXgsdWj77bGL_VwPROimagkxR9lKIfpWixi_L6sGGqN9gcWw8WEvDmAJhgTd96M9guHDnFlIKqSpzccw-uT_8dfvXTA3q9RtPH9eNqyfMy44wJVqZbtnvi4h-MmKS8</recordid><startdate>200308</startdate><enddate>200308</enddate><creator>Lavery, Gareth G</creator><creator>Ronconi, Vanessa</creator><creator>Draper, Nicole</creator><creator>Rabbitt, Elizabeth H</creator><creator>Lyons, Val</creator><creator>Chapman, Karen E</creator><creator>Walker, Elizabeth A</creator><creator>McTernan, Claire L</creator><creator>Giacchetti, Gilberta</creator><creator>Mantero, Franco</creator><creator>Seckl, Jonathan R</creator><creator>Edwards, Christopher R.W</creator><creator>Connell, John M.C</creator><creator>Hewison, Martin</creator><creator>Stewart, Paul M</creator><general>American Heart Association, Inc</general><general>Lippincott</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>200308</creationdate><title>Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene</title><author>Lavery, Gareth G ; Ronconi, Vanessa ; Draper, Nicole ; Rabbitt, Elizabeth H ; Lyons, Val ; Chapman, Karen E ; Walker, Elizabeth A ; McTernan, Claire L ; Giacchetti, Gilberta ; Mantero, Franco ; Seckl, Jonathan R ; Edwards, Christopher R.W ; Connell, John M.C ; Hewison, Martin ; Stewart, Paul M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5392-34b18f927cf3c9ab2f932fd2373a77bd2c0e96c8e5db8a3d0d01cc9aa70b5f153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>11-beta-Hydroxysteroid Dehydrogenase Type 2</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Arterial hypertension. 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Etiology</topic><topic>DNA, Complementary - metabolism</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Genetic Predisposition to Disease</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Hydroxysteroid Dehydrogenases - genetics</topic><topic>Hydroxysteroid Dehydrogenases - metabolism</topic><topic>Hypertension - diagnosis</topic><topic>Hypertension - genetics</topic><topic>Hypokalemia - diagnosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mineralocorticoids - metabolism</topic><topic>Mutation</topic><topic>Pedigree</topic><topic>Phenotype</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lavery, Gareth G</creatorcontrib><creatorcontrib>Ronconi, Vanessa</creatorcontrib><creatorcontrib>Draper, Nicole</creatorcontrib><creatorcontrib>Rabbitt, Elizabeth H</creatorcontrib><creatorcontrib>Lyons, Val</creatorcontrib><creatorcontrib>Chapman, Karen E</creatorcontrib><creatorcontrib>Walker, Elizabeth A</creatorcontrib><creatorcontrib>McTernan, Claire L</creatorcontrib><creatorcontrib>Giacchetti, Gilberta</creatorcontrib><creatorcontrib>Mantero, Franco</creatorcontrib><creatorcontrib>Seckl, Jonathan R</creatorcontrib><creatorcontrib>Edwards, Christopher R.W</creatorcontrib><creatorcontrib>Connell, John M.C</creatorcontrib><creatorcontrib>Hewison, Martin</creatorcontrib><creatorcontrib>Stewart, Paul M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lavery, Gareth G</au><au>Ronconi, Vanessa</au><au>Draper, Nicole</au><au>Rabbitt, Elizabeth H</au><au>Lyons, Val</au><au>Chapman, Karen E</au><au>Walker, Elizabeth A</au><au>McTernan, Claire L</au><au>Giacchetti, Gilberta</au><au>Mantero, Franco</au><au>Seckl, Jonathan R</au><au>Edwards, Christopher R.W</au><au>Connell, John M.C</au><au>Hewison, Martin</au><au>Stewart, Paul M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2003-08</date><risdate>2003</risdate><volume>42</volume><issue>2</issue><spage>123</spage><epage>129</epage><pages>123-129</pages><issn>0194-911X</issn><eissn>1524-4563</eissn><coden>HPRTDN</coden><abstract>ABSTRACT—Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from “essential” hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the HSD11B2 locus can have on blood pressure in later life.</abstract><cop>Philadelphia, PA</cop><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>12860834</pmid><doi>10.1161/01.HYP.0000083340.57063.35</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Hypertension (Dallas, Tex. 1979), 2003-08, Vol.42 (2), p.123-129 |
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| subjects | 11-beta-Hydroxysteroid Dehydrogenase Type 2 Adolescent Adult Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cell Line Clinical manifestations. Epidemiology. Investigative techniques. Etiology DNA, Complementary - metabolism Female Gene Expression Genetic Predisposition to Disease Heterozygote Humans Hydroxysteroid Dehydrogenases - genetics Hydroxysteroid Dehydrogenases - metabolism Hypertension - diagnosis Hypertension - genetics Hypokalemia - diagnosis Male Medical sciences Mineralocorticoids - metabolism Mutation Pedigree Phenotype |
| title | Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene |
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