A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor.
<h4>Background</h4>Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases.<h4>...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/7bae9c93159b40f4b827531676f729e2 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:7bae9c93159b40f4b827531676f729e2 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:7bae9c93159b40f4b827531676f729e22021-11-18T07:51:15ZA novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor.1932-620310.1371/journal.pone.0059537https://doaj.org/article/7bae9c93159b40f4b827531676f729e22013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23560051/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases.<h4>Methods and results</h4>Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells.<h4>Conclusions</h4>We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences.Alexandre PersuMichel LambertJaap DeinumMarta CossuNathalie de VisscherLeonid IrengeJerôme AmbroiseJean-Marc MinonAndrew B NesterovitchAlexander ChurbanovIsolda A PopovaSergei M DanilovA H Jan DanserJean-Luc GalaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e59537 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Alexandre Persu Michel Lambert Jaap Deinum Marta Cossu Nathalie de Visscher Leonid Irenge Jerôme Ambroise Jean-Marc Minon Andrew B Nesterovitch Alexander Churbanov Isolda A Popova Sergei M Danilov A H Jan Danser Jean-Luc Gala A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| description |
<h4>Background</h4>Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases.<h4>Methods and results</h4>Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells.<h4>Conclusions</h4>We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences. |
| format |
article |
| author |
Alexandre Persu Michel Lambert Jaap Deinum Marta Cossu Nathalie de Visscher Leonid Irenge Jerôme Ambroise Jean-Marc Minon Andrew B Nesterovitch Alexander Churbanov Isolda A Popova Sergei M Danilov A H Jan Danser Jean-Luc Gala |
| author_facet |
Alexandre Persu Michel Lambert Jaap Deinum Marta Cossu Nathalie de Visscher Leonid Irenge Jerôme Ambroise Jean-Marc Minon Andrew B Nesterovitch Alexander Churbanov Isolda A Popova Sergei M Danilov A H Jan Danser Jean-Luc Gala |
| author_sort |
Alexandre Persu |
| title |
A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| title_short |
A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| title_full |
A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| title_fullStr |
A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| title_full_unstemmed |
A novel splice-site mutation in angiotensin I-converting enzyme (ACE) gene, c.3691+1G>A (IVS25+1G>A), causes a dramatic increase in circulating ACE through deletion of the transmembrane anchor. |
| title_sort |
novel splice-site mutation in angiotensin i-converting enzyme (ace) gene, c.3691+1g>a (ivs25+1g>a), causes a dramatic increase in circulating ace through deletion of the transmembrane anchor. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/7bae9c93159b40f4b827531676f729e2 |
| work_keys_str_mv |
AT alexandrepersu anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT michellambert anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jaapdeinum anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT martacossu anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT nathaliedevisscher anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT leonidirenge anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeromeambroise anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeanmarcminon anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT andrewbnesterovitch anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT alexanderchurbanov anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT isoldaapopova anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT sergeimdanilov anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT ahjandanser anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeanlucgala anovelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT alexandrepersu novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT michellambert novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jaapdeinum novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT martacossu novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT nathaliedevisscher novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT leonidirenge novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeromeambroise novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeanmarcminon novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT andrewbnesterovitch novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT alexanderchurbanov novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT isoldaapopova novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT sergeimdanilov novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT ahjandanser novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor AT jeanlucgala novelsplicesitemutationinangiotensiniconvertingenzymeacegenec36911gaivs251gacausesadramaticincreaseincirculatingacethroughdeletionofthetransmembraneanchor |
| _version_ |
1718422862219444224 |