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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa
Atherosclerosis, Volume 196, No. 2, Year 2008
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Description
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 S127R and D129G 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. © 2007 Elsevier Ireland Ltd. All rights reserved.
Authors & Co-Authors
Homer, Vivienne M.
New Zealand, Christchurch
Canterbury Health Laboratories
Marais, Adrian David
South Africa, Observatory
Groote Schuur Hospital
Charlton, Francesca
Australia, Sydney
Heart Research Institute Australia
Laurie, Andrew D.
New Zealand, Christchurch
Canterbury Health Laboratories
Hurndell, Nicola
New Zealand, Christchurch
Canterbury Health Laboratories
Scott, R. S.
New Zealand, Christchurch
Canterbury Health Laboratories
Mangili, Fabien
Australia, Sydney
Heart Research Institute Australia
Sullivan, David R.
Australia, Sydney
Royal Prince Alfred Hospital
Barter, Philip J.
Australia, Sydney
Heart Research Institute Australia
Rye, Kerry Anne
Australia, Sydney
Heart Research Institute Australia
George, Peter Myles
New Zealand, Christchurch
Canterbury Health Laboratories
Lambert, Gilles
Australia, Sydney
Heart Research Institute Australia
France, Paris
Inserm
Statistics
Citations: 82
Authors: 12
Affiliations: 5
Identifiers
Doi:
10.1016/j.atherosclerosis.2007.07.022
Study Design
Cohort Study
Study Locations
South Africa