Identificador persistente para citar o vincular este elemento: http://hdl.handle.net/10553/116078
Título: Leu22_Leu23 Duplication at the Signal Peptide of PCSK9 Promotes Intracellular Degradation of LDLr and Autosomal Dominant Hypercholesterolemia
Autores/as: Benito-Vicente, Asier
Uribe, Kepa B.
Larrea-Sebal, Asier
Palacios, Lourdes
Cenarro, Ana
Calle, Xabier
Galicia-Garcia, Unai
Jebari-Benslaiman, Shifa
Sánchez Hernández, Rosa María 
Stef, Marianne
Lambert, Gilles
Civeira, Fernando
Martin, Cesar
Clasificación UNESCO: 32 Ciencias médicas
320702 Artereoesclerosis
321317 Cirugía vascular
Palabras clave: Endoplasmic-Reticulum
Familial Hypercholesterolemia
Protein Translocation
P.Leu167Del Mutation
Secreted Pcsk9, et al.
Fecha de publicación: 2022
Publicación seriada: Arteriosclerosis, Thrombosis, and Vascular Biology 
Resumen: Background: PCSK9 (Proprotein convertase subtilisin/kexin type 9) regulates LDL-C (low-density lipoprotein cholesterol) metabolism by targeting LDLr (LDL receptor) for lysosomal degradation. PCSK9 gain-of-function variants cause autosomal dominant hypercholesterolemia by reducing LDLr levels, the D374Y variant being the most severe, while loss-of-function variants are associated with low LDL-C levels. Gain-of-function and loss-of-function activities have also been attributed to variants occurring in the PCSK9 signal peptide. Among them, L11 is a very rare PCSK9 variant that seems to increase LDL-C values in a moderate way causing mild hypercholesterolemia. Methods: Using molecular biology and biophysics methodologies, activities of L8 and L11 variants, both located in the leucine repetition stretch of the signal peptide, have been extensively characterized in vitro. Results: L8 variant is not associated with increased LDLr activity, whereas L11 activity is increased by approximate to 20% compared with wt PCSK9. The results suggest that the L11 variant reduces LDLr levels intracellularly by a process resulting from impaired cleavage of the signal peptide. This would lead to less efficient LDLr transport to the cell membrane and promote LDLr intracellular degradation. Conclusions: Deletion of a leucine in the signal peptide in L8 variant does not affect PCSK9 activity, whereas the leucine duplication in the L11 variant enhances LDLr intracellular degradation. These findings highlight the importance of deep in vitro characterization of PCSK9 genetic variants to determine pathogenicity and improve clinical diagnosis and therapy of inherited familial hypercholesterolemia disease.
URI: http://hdl.handle.net/10553/116078
ISSN: 1079-5642
DOI: 10.1161/ATVBAHA.122.315499
Fuente: Arteriosclerosis Thrombosis And Vascular Biology [ISSN 1079-5642], v. 42 (7), p. E203-E216, (Julio 2022)
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