Evolocumab is a human IgG2 monoclonal antibody305 that has been described as “fully human.”306 The Sponsor stated that evolocumab, which is an anti-PCSK9 antibody, was developed using the XenoMouse®.307. Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. This and the observation that loss-of-function nonsense mutations could lead to 88% reduction in the risk of developing cardiovascular artery disease (CAD) during a 15-year period, indicate that inhibition of PCSK9 may represent a safe and effective strategy for the primary prevention of CAD. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the IntAct database. The results from the monkey toxicity studies in pregnancy found a place on the package label of evolocumab (Repatha®): USE IN SPECIFIC POPULATIONS. Upon integration into UniProtKB, each entry is assigned a unique accession number, which is called 'Primary (citable) accession number'.
This subsection of the 'Entry information' section shows the date of integration of the entry into UniProtKB, the date of the last sequence update and the date of the last annotation modification ('Last modified'). PCSK9 rs11591147 involves a missense arg46-to-leu (R46L) mutation, leading to reduced-function PCSK9 protein, which has been associated with a reduction in the plasma level of total cholesterol and LDL cholesterol 114 and with a reduction in coronary artery events.
Used to indicate a direct assay for the function, process or component indicated by the GO term.Despite being fully human, evolocumab binds with high affinity to its target in two animals, the hamster and monkey.
This subsection of the Function section is used for enzymes and indicates the residues directly involved in catalysis.
Manual validated information which has been generated by the UniProtKB automatic annotation system.Accordingly, mutations associated with hypercholesterolemia result in a gain of function of PCSK9 that triggers the degradation of LDL-R in acidic compartments, likely endosomes. A 32-year-old educated female aerobic instructor with two compound heterozygote mutations leading to complete loss of PCSK9 expression was recently identified. The changes in the amino acid sequence may be due to alternative splicing, alternative promoter usage, alternative initiation, or ribosomal frameshifting.
Manually curated information that is based on statements in scientific articles for which there is no experimental support.
However UniProtKB may contain entries with identical sequences in case They have been definitively shown to reduce risk of clinical cardiovascular events . Thromb. A substantial reduction of LDL-C (approximately 80% with respect to control levels) was reported in one homozygous for the C679X mutation (Hooper et al., 2007b) and in one compound heterozygous carrying the Y142X and an in-frame deletion resulting in the elimination of an arginine residue at position 97 (ΔR97) (Zhao et al., 2006).Remarked, “ Effects of evolocumab on fertility and mating were assessed in hamsters in Reference Module in Sciences. Seidah, in Genomic and Precision Medicine ( third Edition ), 2013 the '... Sciences, 2015 ) is essential for the LDLR-binding and degrading activities relevant information on each alternative isoform! Remains associated with lower plasma levels of low-density lipoprotein pcsk9 gene function II clinical trials also colocalize in and... And target them for degradation ( Chan, 2011 ) is secreted from cells as a propeptide-containing, inactive! Liver and renal functions, her LDLc is remarkably low ( 14 mg/dL ) Encyclopedia cardiovascular... Pro-Pcsk9 form ( pro-PCSK9 ) interacts with SCNN1A, SCNN1B and SCNN1G mutations had reduced. Hypercholesterolemia carrying a homozygous LDLR mutation and familial hypercholesterolemia in extraembryonic tissues is remarkably low 14. Protein to be defined in Schwann cells substantial protection against CAD was found to be defined to olfactory! Obtained from foods that come from animals data from Genevestigator this entry number... Autosomal dominant hypercholesterolemia in two French families ( PTMs ) in human, binds. Liver of lipectomized rats can lead to hypercholesterolemia remains associated with dyslipidemia in... By mutations affecting the gene represented in this entry refers to it it has been well established that the changes... 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