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Human Molecular Genetics Advance Access originally published online on March 16, 2005
Human Molecular Genetics 2005 14(9):1161-1169; doi:10.1093/hmg/ddi128
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia

Xi-Ming Sun1,{dagger}, Emily R. Eden1,{dagger}, Isabella Tosi1, Clare K. Neuwirth1, David Wile2, Rossi P. Naoumova1 and Anne K. Soutar1,*

1MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK and 2Department of Clinical Biochemistry, University Hospital, Aintree, Liverpool L9 7AL, UK

* To whom correspondence should be addressed. Tel: +44 2083832324; Fax: +44 2083832077; Email: anne.soutar{at}csc.mrc.ac.uk

Received January 11, 2005; Revised February 7, 2005; Accepted March 10, 2005

Typically, autosomal dominant familial hypercholesterolaemia (FH) is caused by mutations in the low density lipoprotein (LDL) receptor or apolipoprotein B genes that result in defective clearance of plasma LDL by the liver, but a third gene (PCSK9), encoding a putative proprotein convertase, has recently been implicated. Two independent microarray studies support a role for PCSK9 in sterol metabolism and adenoviral-mediated over-expression of PCSK9 in mouse liver depletes hepatic LDL-receptor protein, but the mechanism by which dominant mutations cause human FH is unclear. We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor. We have stably expressed wild-type (WT) and variant PCSK9 in McArdle-7777 rat hepatoma cells and shown by confocal microscopy that all forms of PCSK9 co-localize with protein disulphide isomerase in the ER whether or not they can be autocleaved. Expression of the proposed pathogenic variants, but not of WT, S386A or F216L PCSK9, increases secretion of apolipoprotein B100-containing lipoproteins from the cells by 2–4-fold probably by reducing the degradation of nascent protein; no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants. This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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