Abstract:
BACKGROUND:The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR. METHODS:In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied. RESULTS:Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. CONCLUSION:These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target.
journal_name
Atherosclerosisjournal_title
Atherosclerosisauthors
Abifadel M,Guerin M,Benjannet S,Rabès JP,Le Goff W,Julia Z,Hamelin J,Carreau V,Varret M,Bruckert E,Tosolini L,Meilhac O,Couvert P,Bonnefont-Rousselot D,Chapman J,Carrié A,Michel JB,Prat A,Seidah NG,Boileau Cdoi
10.1016/j.atherosclerosis.2012.04.006subject
Has Abstractpub_date
2012-08-01 00:00:00pages
394-400issue
2eissn
0021-9150issn
1879-1484pii
S0021-9150(12)00257-2journal_volume
223pub_type
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