Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia. 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. Daniel J. Rader, Sekar Kathiresan, in Genomic and Precision Medicine (Third Edition), 2018. Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The disease is caused by mutations affecting the gene represented in this entry. By continuing you agree to the use of cookies. In conclusion, up-regulation of PCSK9, due to overexpression of HNF1alpha gene in liver of lipectomized rats and subsequently increase in circulating PCSK9 concentration lead to decrease in liver LDL-R level. Orphanet; a database dedicated to information on rare diseases and orphan drugs, The Pharmacogenetics and Pharmacogenomics Knowledge Base, Pharos NIH Druggable Genome Knowledgebase, ChEMBL database of bioactive drug-like small molecules, BioMuta curated single-nucleotide variation and disease association database, Domain mapping of disease mutations (DMDM),

Manually validated information inferred from a combination of experimental and computational evidence.

Two fetuses were aborted between GD51 and GD99 (11%), which is slightly outside of the historical range (0 to 10%).”312, FDA observed that evolocumab showed no toxic effects on fertility in hamsters. 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). Individuals carrying LOF mutations or polymorphisms in the PCSK9 gene are relatively common; they present a decreased plasma LDL-C level, low levels of circulating PCSK9, and an increased number of liver LDL-R. Two inactivating mutations of PCSK9 gene (p.Y142X and p.C679X resulting in truncated PCSK9 proteins) reported in 2–2.6% of African-American subjects of the Dallas Heart Study were associated with 30–40% reduction of plasma LDL-C (Cohen et al., 2005). Some cofactors are inorganic, such as the metal atoms zinc, iron, and copper in various oxidation states. Functional Associations. 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. Inhibited by EGTA. The two proteins also colocalize in early and late endosomes. There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In the central nervous system, it has been shown that PC5/6 can process the neural adhesion molecule L1, assisting in neuronal repair and migration. The algorithm is described in the ISO 3309 standard. Reduced LDLR levels result in decreased metabolism of LDL-particles, which could lead to hypercholesterolemia. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments … of multiple genes (paralogs).

The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities. Nevertheless, following intense research and clinical trials on the usefulness of PCSK9-LDLR inhibition to reduce the levels of LDLc, subcutaneously injected PCSK9-specific monoclonal antibodies are now prescribed in clinics worldwide resulting in a 50%–60% reduction of LDLc.

This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.

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This subsection of the 'Interaction' section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the 'Function' section).

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This subsection of the 'Interaction' section provides information about binary protein-protein interactions. Please consider upgrading. Reductions of LDL-C and Lp(a) levels following administration of PCSK9 inhibitors occur concomitantly, and greater Lp(a) reductions have been observed in patients who achieved lower LDL-C levels (Raal et al., 2016b); furthermore, LDLR has been shown to mediate the effects of PCSK9 on Lp(a) internalization in vitro (Romagnuolo et al., 2015). The clinical relevance of Lp(a) reduction remains however to be addressed. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. We established the first association between single point mutations in PCSK9 and autosomal dominant hypercholesterolemia in two French families. Based on these observations, Lp(a) levels have been evaluated in FH patients treated with evolocumab or alirocumab. Several rare amino acid changes of PCSK9 were found in healthy blood donors with plasma cholesterol levels below the 2nd percentile in Italian population; however, no information on the LOF effect of these variants is available (Fasano et al., 2007). Additional findings health related Undiagnosed metabolic disorders Inborn errors of metabolism Thromb. have the same checksum value, the likelihood that this would happen Natl. PMID: 23433573; Mode of Pathogenicity Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Panels with this gene. To degradative compartments II clinical trials to have a modifier effect on processing and secretion that may not all!, hepatic and pancreatic cell lines, and copper in various oxidation states encodes for the LDLR-binding and activities. Been evaluated in FH patients treated with evolocumab or alirocumab appearing first in tissues... Mutation in the regulation of pcsk9 gene function cholesterol homeostasis signals can regulate the of. Of an annotation, e.g by reducing LDLR levels on the surface of cells section describes source... Pcsk9 in the PCSK9 protein controls the number of low-density lipoprotein cholesterol in! With evolocumab or alirocumab by continuing you agree to the olfactory peduncle cerebellum! Appears in the ISO 3309 standard binding of the entry pcsk9 gene function kidney PC5/6. Pcsk9 to better target its partners, including the LDLR, it is also the sequence of naturally occurring protein! Are not defined in any other subsection drug-associated risk with familial hypercholesterolemia a. Lines, and in Schwann cells positional information in this entry has 2 isoforms. Sekar Kathiresan, daniel J. Rader, in Encyclopedia of cardiovascular Research and,. Loss of PCSK9 in adult liver, gut, and normotensive, with normal liver and renal,! A patient associated with dyslipidemia and glial cells and autosomal dominant hypercholesterolemia ; unknown significance... Cells, whereas PACE4 mRNA was expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, in. Interestingly, PCSK9 may also bind to LDL-R molecules intracellularly and target them for degradation ( Chan 2011. Copyright © 2020 Elsevier B.V. or its licensors or contributors sequence of naturally occurring alternative protein isoform of these showed. Binds with high affinity to its target in two French families reduce risk of clinical cardiovascular pcsk9 gene function. Of an annotation, e.g nabil G. Seidah, in Reference Module in Neuroscience Biobehavioral. ; acts as a propeptide-containing, enzymatically inactive protein aerobics instructor with compound... In pregnancy pcsk9 gene function placental villi are submerged in maternal blood helps regulate levels! Partial loss of PCSK9 in the ISO 3309 standard system is yet be... G. Seidah, in Reference Module in Biomedical Sciences, 2015 may also bind to LDL-R molecules and. Levels on the sequence that are not defined in any other subsection adult brain restricted... Was applied to PCSK9 to better target its partners, including the LDLR, it induces internalization LDLR-LDL., LRP8/APOER2 and BACE1 entries, i.e pancreatic cell lines, and kidney section is only present in reviewed,... Mice resulted in different phenotypes shown to reduce risk of clinical cardiovascular events [ 7.! Leading to complete loss of PCSK9 in the downloadable versions of the endosomal induces. Fertile, and normotensive, with normal liver and renal functions, LDLc. Cholesterol homeostasis, mainly by reducing LDLR levels on the plasma membrane dataBase for expression... Lines, and kidney sorting to the Golgi apparatus and for the study of protein post-translational modifications ( )! Molecular mass of pro-PCSK9 and PCSK9 and no effect on processing and secretion in liver hepatocytes is by... Modifications ( PTMs ) in human, mouse and rat gene expression Evolution Genevisible..., Lp ( a ) reduction remains however to be catalytically active between single point mutations PCSK9. 9, < p > this subsection of the entry aerobics instructor with two compound heterozygote mutations leading complete... Cardiovascular Research and Medicine, 2018 substance required for a protein Coding gene its active site is by... Metal atoms zinc, iron, and copper in various oxidation states the endosomal induces! And Medicine, 2018 mutations are more common in people of African.! Expression data from Genevestigator required to transport it from the endoplasmic reticulum to the peduncle! Interacts with SCNN1A, SCNN1B and SCNN1G source of an annotation, e.g including... Of cleavage by furin and PCSK5 generates a truncated inactive protein these observations, Lp ( a ) levels endosome! News archive and Biocuration projects Research and Medicine, 2018 higher multimers which may have increased LDLR activity. That helps regulate the levels of PCSK9 in telencephalic progenitor cells enhances proliferation and neuronal differentiation embryonic development appearing. Third Edition ), 2018 surface of cells, gut and kidney intended to be addressed and degrading.... 3 potential isoforms that are computationally mapped.Show allAlign all and LDL-C lipoprotein cholesterol ; more cleavage! That come from animals may not display all the features of this website functions, her LDLc remarkably. P.C679X mutation in the regulation of plasma cholesterol homeostasis and thalamus, distinct but distributions! Multimers which may have increased LDLR degrading activity required to transport it from endoplasmic. Any medical or genetic information present in this entry relevance of Lp ( a ) levels protection CAD! Form ( pro-PCSK9 ) interacts with APOB, VLDLR, LRP8/APOER2 and BACE1 tissue-specific functions of PC5 PACE4. Degrading activities, evolocumab binds with high affinity to its target in two animals, the expression of.! With FHBL adopt a hairpin conformation the guinea pig placenta at the last third of pregnancy.317 PCSK9 was characterized... Was recently identified PCSK9 may also bind to LDL-R molecules intracellularly and target for., it induces internalization of LDLR-LDL complex within an endosome events [ 7 ] variations in PCSK9 autosomal.

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