Identificador persistente para citar o vincular este elemento: http://hdl.handle.net/10553/70019
Título: The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9
Autores/as: Sánchez Hernández, Rosa María 
Di Taranto, Maria Donata
Benito-Vicente, Asier
Uribe, Kepa B.
Lamiquiz-Moneo, Itziar
Larrea-Sebal, Asier
Jebari, Shifa
Galicia-Garcia, Unai
Nóvoa, F. Javier
Boronat, Mauro 
Wägner, Ana M. 
Civeira, Fernando
Martín, César
Fortunato, Giuliana
Clasificación UNESCO: 320704 Patología cardiovascular
Palabras clave: Cholesterol
Dyslipemia
Familial Hypercholesterolemia
Functional Assay
Gene Expression, et al.
Fecha de publicación: 2019
Publicación seriada: Atherosclerosis 
Resumen: Background and aims: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy. Methods: We studied familial segregation and determined variant activity in vitro. Results: We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. Conclusions: We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability.
URI: http://hdl.handle.net/10553/70019
ISSN: 0021-9150
DOI: 10.1016/j.atherosclerosis.2019.08.020
Fuente: Atherosclerosis [ISSN 0021-9150],v. 289, p. 162-172
Colección:Artículos
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