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A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy
The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a pre...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (5), p.1388-1393 |
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creator | Haghighi, Kobra Kolokathis, Fotis Gramolini, Anthony O. Waggoner, Jason R. Pater, Luke Lynch, Roy A. Fan, Guo-Chang Tsiapras, Dimitris Parekh, Rohan R. Dorn, Gerald W. MacLennan, David H. Kremastinos, Dimitrios Th Kranias, Evangelia G. |
description | The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca²⁺-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca²⁺-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice. |
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Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca²⁺-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca²⁺-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0510519103</identifier><identifier>PMID: 16432188</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adult ; Animals ; Antibodies ; Arginine - genetics ; Arrhythmias, Cardiac - metabolism ; Biological Sciences ; Calcium ; Calcium - chemistry ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cardiomyopathies ; Cardiomyopathies - genetics ; Cardiomyopathies - mortality ; Cell Line ; Cellular immunity ; Child ; Dilated cardiomyopathy ; DNA Mutational Analysis ; Echocardiography ; Electrocardiography ; Family Health ; Female ; Gene Deletion ; Gene expression ; Genetic mutation ; Genetics ; Heart ; Heart failure ; Heterozygote ; Homozygote ; Humans ; Male ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence ; Middle Aged ; Models, Statistical ; Mutation ; Pedigree ; Phosphorylation ; Proteins ; Sarcoplasmic Reticulum - metabolism ; Time Factors ; Transgenic animals ; Ventricular tachycardia</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2006-01, Vol.103 (5), p.1388-1393</ispartof><rights>Copyright 2006 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jan 31, 2006</rights><rights>Copyright © 2006, The National Academy of Sciences 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-4cd273fa0f402eb37e0d0b2dffeda2c8aeb23c73bed09101b2ab1be1968fa2203</citedby><cites>FETCH-LOGICAL-c592t-4cd273fa0f402eb37e0d0b2dffeda2c8aeb23c73bed09101b2ab1be1968fa2203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/103/5.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/30048382$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/30048382$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829,58593,58826</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16432188$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Haghighi, Kobra</creatorcontrib><creatorcontrib>Kolokathis, Fotis</creatorcontrib><creatorcontrib>Gramolini, Anthony O.</creatorcontrib><creatorcontrib>Waggoner, Jason R.</creatorcontrib><creatorcontrib>Pater, Luke</creatorcontrib><creatorcontrib>Lynch, Roy A.</creatorcontrib><creatorcontrib>Fan, Guo-Chang</creatorcontrib><creatorcontrib>Tsiapras, Dimitris</creatorcontrib><creatorcontrib>Parekh, Rohan R.</creatorcontrib><creatorcontrib>Dorn, Gerald W.</creatorcontrib><creatorcontrib>MacLennan, David H.</creatorcontrib><creatorcontrib>Kremastinos, Dimitrios Th</creatorcontrib><creatorcontrib>Kranias, Evangelia G.</creatorcontrib><title>A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca²⁺-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca²⁺-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.</description><subject>Adult</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Arginine - genetics</subject><subject>Arrhythmias, Cardiac - metabolism</subject><subject>Biological Sciences</subject><subject>Calcium</subject><subject>Calcium - chemistry</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cardiomyopathies</subject><subject>Cardiomyopathies - genetics</subject><subject>Cardiomyopathies - mortality</subject><subject>Cell Line</subject><subject>Cellular immunity</subject><subject>Child</subject><subject>Dilated cardiomyopathy</subject><subject>DNA Mutational Analysis</subject><subject>Echocardiography</subject><subject>Electrocardiography</subject><subject>Family Health</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>Gene expression</subject><subject>Genetic mutation</subject><subject>Genetics</subject><subject>Heart</subject><subject>Heart failure</subject><subject>Heterozygote</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Fluorescence</subject><subject>Middle Aged</subject><subject>Models, Statistical</subject><subject>Mutation</subject><subject>Pedigree</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><subject>Time Factors</subject><subject>Transgenic animals</subject><subject>Ventricular tachycardia</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqFkd2LEzEUxQdR3Lr67JMSfNCXdvfmY75ehFJ1K1QU0eeQmbnTSZlJZpOM2P_e1Jbt6oNCIIT7O4d7cpLkOYUrCjm_Ho3yV5DSeEoK_EEyo1DSRSZKeJjMAFi-KAQTF8kT73cAUKYFPE4uaCY4o0UxS8ySfJqCCtoaog0JHZL1NChDvnTWj53t1VDF1w0anJN32GPQZkuWbquNNkiomJOv6Kc--IN8g6FT_Zys0WGjg3J7slKu0XbY21GFbv80edSq3uOz032ZfP_w_ttqvdh8vvm4Wm4WdVqysBB1w3LeKmgFMKx4jtBAxZq2xUaxulBYMV7nvMImxgVaMVXRCmmZFa1iDPhl8vboO07VgE2NJjjVy9HpIS4lrdLyz4nRndzaH5LyDNIiiwavTwbO3k7ogxy0r7HvlUE7eZlDLgTn5X9BmouMlkUawVd_gTs7ORN_QTKgXAhGeYSuj1DtrPcO27uVKchD4_LQuDw3HhUv7yc986eK7wEH5dmOyzSm_Q28-Scg26nvA_4MkXxxJHc-WHeHcgBR8ILxX0qtyZU</recordid><startdate>20060131</startdate><enddate>20060131</enddate><creator>Haghighi, Kobra</creator><creator>Kolokathis, Fotis</creator><creator>Gramolini, Anthony O.</creator><creator>Waggoner, Jason R.</creator><creator>Pater, Luke</creator><creator>Lynch, Roy A.</creator><creator>Fan, Guo-Chang</creator><creator>Tsiapras, Dimitris</creator><creator>Parekh, Rohan R.</creator><creator>Dorn, Gerald W.</creator><creator>MacLennan, David H.</creator><creator>Kremastinos, Dimitrios Th</creator><creator>Kranias, Evangelia G.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060131</creationdate><title>A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy</title><author>Haghighi, Kobra ; Kolokathis, Fotis ; Gramolini, Anthony O. ; Waggoner, Jason R. ; Pater, Luke ; Lynch, Roy A. ; Fan, Guo-Chang ; Tsiapras, Dimitris ; Parekh, Rohan R. ; Dorn, Gerald W. ; MacLennan, David H. ; Kremastinos, Dimitrios Th ; Kranias, Evangelia G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-4cd273fa0f402eb37e0d0b2dffeda2c8aeb23c73bed09101b2ab1be1968fa2203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adult</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Arginine - genetics</topic><topic>Arrhythmias, Cardiac - metabolism</topic><topic>Biological Sciences</topic><topic>Calcium</topic><topic>Calcium - chemistry</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cardiomyopathies</topic><topic>Cardiomyopathies - genetics</topic><topic>Cardiomyopathies - mortality</topic><topic>Cell Line</topic><topic>Cellular immunity</topic><topic>Child</topic><topic>Dilated cardiomyopathy</topic><topic>DNA Mutational Analysis</topic><topic>Echocardiography</topic><topic>Electrocardiography</topic><topic>Family Health</topic><topic>Female</topic><topic>Gene Deletion</topic><topic>Gene expression</topic><topic>Genetic mutation</topic><topic>Genetics</topic><topic>Heart</topic><topic>Heart failure</topic><topic>Heterozygote</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Fluorescence</topic><topic>Middle Aged</topic><topic>Models, Statistical</topic><topic>Mutation</topic><topic>Pedigree</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Sarcoplasmic Reticulum - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Haghighi, Kobra</au><au>Kolokathis, Fotis</au><au>Gramolini, Anthony O.</au><au>Waggoner, Jason R.</au><au>Pater, Luke</au><au>Lynch, Roy A.</au><au>Fan, Guo-Chang</au><au>Tsiapras, Dimitris</au><au>Parekh, Rohan R.</au><au>Dorn, Gerald W.</au><au>MacLennan, David H.</au><au>Kremastinos, Dimitrios Th</au><au>Kranias, Evangelia G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2006-01-31</date><risdate>2006</risdate><volume>103</volume><issue>5</issue><spage>1388</spage><epage>1393</epage><pages>1388-1393</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Contributed by David H. MacLennan, December 9, 2005</notes><notes>Conflict of interest statement: No conflicts declared.</notes><notes>Author contributions: K.H., F.K., A.O.G., R.A.L., G.-C.F., D.T., G.W.D., D.H.M., D.T.K., and E.G.K. designed research; K.H., F.K., A.O.G., J.R.W., L.P., G.-C.F., D.T., and D.T.K. performed research; F.K., A.O.G., D.T., and D.T.K. contributed new reagents/analytic tools; K.H., F.K., A.O.G., J.R.W., L.P., R.A.L., G.-C.F., D.T., R.R.P., G.W.D., D.H.M., D.T.K., and E.G.K. analyzed data; and K.H., F.K., A.O.G., R.A.L., G.-C.F., D.T., G.W.D., D.H.M., D.T.K., and E.G.K. wrote the paper.</notes><notes>Abbreviations: DCM, dilated cardiomyopathy; ECG, electrocardiogram; PLN, phospholamban; SERCA2a, sarcoplasmic reticulum Ca2+-ATPase; SR, sarcoplasmic reticulum.</notes><notes>To whom correspondence may be addressed. E-mail: david.maclennan@utoronto.ca or litsa.kranias@uc.edu.</notes><abstract>The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca²⁺-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca²⁺-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>16432188</pmid><doi>10.1073/pnas.0510519103</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Animals Antibodies Arginine - genetics Arrhythmias, Cardiac - metabolism Biological Sciences Calcium Calcium - chemistry Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cardiomyopathies Cardiomyopathies - genetics Cardiomyopathies - mortality Cell Line Cellular immunity Child Dilated cardiomyopathy DNA Mutational Analysis Echocardiography Electrocardiography Family Health Female Gene Deletion Gene expression Genetic mutation Genetics Heart Heart failure Heterozygote Homozygote Humans Male Mice Mice, Transgenic Microscopy, Fluorescence Middle Aged Models, Statistical Mutation Pedigree Phosphorylation Proteins Sarcoplasmic Reticulum - metabolism Time Factors Transgenic animals Ventricular tachycardia |
title | A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy |
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