PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

Guo, Qianyun; Feng, Xunxun; Zhou, Yujie

doi:10.3389/fgene.2020.01020

Cited by 35 publications

(24 citation statements)

References 140 publications

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“…Furthermore, gain of function (GOF) mutations in PCSK9 genes are the cause of familial hypercholesterolemia with significantly higher levels of cholesterol in the blood [ 7 ], whereas loss-of-function mutations (LOF) are associated with hypocholesterolemia [ 8 ]. Table 2 presents the most frequent mutations of PCSK9 that naturally occur [ 8 , 9 ].…”

Section: Pcsk9 and Its Inhibitorsmentioning

confidence: 99%

Insight into the Evolving Role of PCSK9

et al. 2022

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

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Section: Pcsk9 and Its Inhibitorsmentioning

confidence: 99%

Insight into the Evolving Role of PCSK9

et al. 2022

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“…Evidence has shown that a gain-of-function variant of PCSK9 is linked to a high level of blood low-density lipoprotein cholesterol (LDL-C) (Seidah et al, 2014), a primary cause of cardiovascular diseases. In contrast, people carrying loss-of-function PCSK9 variants are asymptomatic, showing lower levels of LDL-C and reduced risks of cardiovascular diseases (Guo et al, 2020b). Ding et al (2014a) delivered Cas9/SgRNA targeting Pcsk9 into the mouse liver via injection of AAV8 particles.…”

Section: Gene Editing In Liver Gene Therapymentioning

confidence: 99%

Gene editing and its applications in biomedicine

Zhuang

et al. 2022

Sci. China Life Sci.

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The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats (CRISPR) and programmable nucleases to make precise modifications to genetic material, has provided enormous opportunities to advance biomedical research and promote human health. The application of these technologies in basic biomedical research has yielded significant advances in identifying and studying key molecular targets relevant to human diseases and their treatment. The clinical translation of genome editing techniques offers unprecedented biomedical engineering capabilities in the diagnosis, prevention, and treatment of disease or disability. Here, we provide a general summary of emerging biomedical applications of genome editing, including open challenges. We also summarize the tools of genome editing and the insights derived from their applications, hoping to accelerate new discoveries and therapies in biomedicine.

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“…PCSK9 is highly conserved among mammals, including chimpanzee, monkey, camel, alpaca, rat, and mouse, with an approximate amino acid identity of 99, 96, 82, 81, 77, and 77%, respectively. The majority of identified gain-of-function and loss-of-function mutations occur in entirely conserved residues, such as gain-of-function mutations D35Y, L108R, S127R, D129G, N157K, R215H, F216L, R218S, A220T, R357H, D374Y, N425S, R468W, R496W and R499H, and lossof-function mutations R104C, R105Q, G106R, G236S, L253F, G316C, N354I and S462P (2, 4,11,12). However, loss-of-function mutations R46L and R93C and gain-of-function mutations R96L, A168E, R499H, and S636R are not conserved between human and mouse or rat PCSK9.…”

Section: Pcsk9 Functionmentioning

confidence: 99%

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Xia

Peng

et al. 2021

Front. Cardiovasc. Med.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptor (LDLR) and plays a central role in regulating plasma levels of LDL cholesterol levels, lipoprotein(a) and triglyceride-rich lipoproteins, increasing the risk of cardiovascular disease. Additionally, PCSK9 promotes degradation of major histocompatibility protein class I and reduces intratumoral infiltration of cytotoxic T cells. Inhibition of PCSK9 increases expression of LDLR, thereby reducing plasma levels of lipoproteins and the risk of cardiovascular disease. PCSK9 inhibition also increases cell surface levels of major histocompatibility protein class I in cancer cells and suppresses tumor growth. Therefore, PCSK9 plays a vital role in the pathogenesis of cardiovascular disease and cancer, the top two causes of morbidity and mortality worldwide. Monoclonal anti-PCSK9 antibody-based therapy is currently the only available treatment that can effectively reduce plasma LDL-C levels and suppress tumor growth. However, high expenses limit their widespread use. PCSK9 promotes lysosomal degradation of its substrates, but the detailed molecular mechanism by which PCSK9 promotes degradation of its substrates is not completely understood, impeding the development of more cost-effective alternative strategies to inhibit PCSK9. Here, we review our current understanding of PCSK9 and focus on the regulation of its expression and functions.

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PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

Cited by 35 publications

References 140 publications

Insight into the Evolving Role of PCSK9

Insight into the Evolving Role of PCSK9

Gene editing and its applications in biomedicine

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

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