AustralieFrV1, Main, Exploration, bibRecord, 008C80

Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa

Identifieur interne : 008C80 ( Main/Exploration ); précédent : 008C79; suivant : 008C81

Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa

Auteurs : Vivienne M. Homer [Nouvelle-Zélande] ; A. David Marais [Afrique du Sud] ; Francesca Charlton [Australie] ; Andrew D. Laurie [Nouvelle-Zélande] ; Nicola Hurndell [Nouvelle-Zélande] ; Russel Scott [Nouvelle-Zélande] ; Fabien Mangili [Australie] ; David R. Sullivan [Australie] ; Philip J. Barter [Australie] ; Kerry-Anne Rye [Australie] ; Peter M. George [Nouvelle-Zélande] ; Gilles Lambert [Australie, France]

Source :

Atherosclerosis [ 0021-9150 ] ; 2008.

RBID : Pascal:08-0197069

Descripteurs français

Pascal (Inist)
- Maladie héréditaire, Hypercholestérolémie, Pathologie de l'appareil circulatoire, Athérosclérose, Afrique du Sud, Lipoprotéine LDL, Cholestérol, Lipide.
Wicri :
- geographic : Afrique du Sud.

English descriptors

KwdEn :
- Atherosclerosis, Cardiovascular disease, Cholesterol, Genetic disease, Hypercholesterolemia, Lipids, Lipoprotein LDL, South Africa.

Abstract

We analysed the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) exons and intronic junctions of 71 patients with familial hypercholesterolemia (FH) in whom LDL receptor (LDLR) or apolipoprotein B100 mutations were excluded. The previously reported S127R and R237W mutations were found in South African families, whereas new missense mutations D129G and A168E were found in families from New Zealand. Only, the S127R and D129G mutations modify a highly conserved residue and segregate with the FH phenotype. We overexpressed those mutants in hepatoma cells and found that both S 127R and D 129G have reduced autocatalytic activity compared with wild-type PCSK9, whereas the A168E mutant is processed normally. The S127R and D129G mutants were not secreted from cells, unlike the A168E mutant and wild-type PCSK9. By immunoblot, we showed that the expression of the LDLR was reduced by 40% in cells overexpressing wild-type or A168E PCSK9 and further reduced by 30% when the S127R or D129G mutants were used. Paralleling the LDLR levels, LDL cellular binding decreased by 25% upon wild-type PCSK9 or A168E overexpression, and by 45% with both S127R and D129G mutants. Our study therefore indicates that PCSK9 mediated inhibition of the LDLR does not require PCSK9 autocatalytic cleavage or secretion, suggesting that PCSK9 may also function intracellularly.

Affiliations:

Links toward previous steps (curation, corpus...)

to stream PascalFrancis, to step Corpus: 003645
to stream PascalFrancis, to step Curation: 002A01
to stream PascalFrancis, to step Checkpoint: 003176
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Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa</title>
<author><name sortKey="Homer, Vivienne M" sort="Homer, Vivienne M" uniqKey="Homer V" first="Vivienne M." last="Homer">Vivienne M. Homer</name>
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<author><name sortKey="Mangili, Fabien" sort="Mangili, Fabien" uniqKey="Mangili F" first="Fabien" last="Mangili">Fabien Mangili</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>The Heart Research Institute, 114 Pyrmont Bridge Road, Camperdown</s1>
<s2>Sydney, NSW 2050</s2>
<s3>AUS</s3>
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<author><name sortKey="Sullivan, David R" sort="Sullivan, David R" uniqKey="Sullivan D" first="David R." last="Sullivan">David R. Sullivan</name>
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<s3>AUS</s3>
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</placeName>
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<author><name sortKey="Barter, Philip J" sort="Barter, Philip J" uniqKey="Barter P" first="Philip J." last="Barter">Philip J. Barter</name>
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</affiliation>
</author>
<author><name sortKey="Rye, Kerry Anne" sort="Rye, Kerry Anne" uniqKey="Rye K" first="Kerry-Anne" last="Rye">Kerry-Anne Rye</name>
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</author>
<author><name sortKey="George, Peter M" sort="George, Peter M" uniqKey="George P" first="Peter M." last="George">Peter M. George</name>
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<author><name sortKey="Lambert, Gilles" sort="Lambert, Gilles" uniqKey="Lambert G" first="Gilles" last="Lambert">Gilles Lambert</name>
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<s2>Sydney, NSW 2050</s2>
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</affiliation>
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<s2>Nantes</s2>
<s3>FRA</s3>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>France</country>
<placeName><region type="region">Pays de la Loire</region>
<region type="old region">Pays de la Loire</region>
<settlement type="city">Nantes</settlement>
</placeName>
</affiliation>
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</analytic>
<series><title level="j" type="main">Atherosclerosis</title>
<title level="j" type="abbreviated">Atherosclerosis</title>
<idno type="ISSN">0021-9150</idno>
<imprint><date when="2008">2008</date>
</imprint>
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<seriesStmt><title level="j" type="main">Atherosclerosis</title>
<title level="j" type="abbreviated">Atherosclerosis</title>
<idno type="ISSN">0021-9150</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Atherosclerosis</term>
<term>Cardiovascular disease</term>
<term>Cholesterol</term>
<term>Genetic disease</term>
<term>Hypercholesterolemia</term>
<term>Lipids</term>
<term>Lipoprotein LDL</term>
<term>South Africa</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Maladie héréditaire</term>
<term>Hypercholestérolémie</term>
<term>Pathologie de l'appareil circulatoire</term>
<term>Athérosclérose</term>
<term>Afrique du Sud</term>
<term>Lipoprotéine LDL</term>
<term>Cholestérol</term>
<term>Lipide</term>
</keywords>
<keywords scheme="Wicri" type="geographic" xml:lang="fr"><term>Afrique du Sud</term>
</keywords>
</textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en">We analysed the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) exons and intronic junctions of 71 patients with familial hypercholesterolemia (FH) in whom LDL receptor (LDLR) or apolipoprotein B100 mutations were excluded. The previously reported S127R and R237W mutations were found in South African families, whereas new missense mutations D129G and A168E were found in families from New Zealand. Only, the S127R and D129G mutations modify a highly conserved residue and segregate with the FH phenotype. We overexpressed those mutants in hepatoma cells and found that both S 127R and D 129G have reduced autocatalytic activity compared with wild-type PCSK9, whereas the A168E mutant is processed normally. The S127R and D129G mutants were not secreted from cells, unlike the A168E mutant and wild-type PCSK9. By immunoblot, we showed that the expression of the LDLR was reduced by 40% in cells overexpressing wild-type or A168E PCSK9 and further reduced by 30% when the S127R or D129G mutants were used. Paralleling the LDLR levels, LDL cellular binding decreased by 25% upon wild-type PCSK9 or A168E overexpression, and by 45% with both S127R and D129G mutants. Our study therefore indicates that PCSK9 mediated inhibition of the LDLR does not require PCSK9 autocatalytic cleavage or secretion, suggesting that PCSK9 may also function intracellularly.</div>
</front>
</TEI>
<affiliations><list><country><li>Afrique du Sud</li>
<li>Australie</li>
<li>France</li>
<li>Nouvelle-Zélande</li>
</country>
<region><li>Nouvelle-Galles du Sud</li>
<li>Pays de la Loire</li>
</region>
<settlement><li>Nantes</li>
<li>Sydney</li>
</settlement>
</list>
<tree><country name="Nouvelle-Zélande"><noRegion><name sortKey="Homer, Vivienne M" sort="Homer, Vivienne M" uniqKey="Homer V" first="Vivienne M." last="Homer">Vivienne M. Homer</name>
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   |texte=   Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa
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	Serveur d'exploration sur les relations entre la France et l'Australie
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Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa

Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa

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