What is a PCSK9 mutation?
Abstract. Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a newly-identified circulating protein in cholesterol metabolism in mammals, including humans, which has emerged as a new pharmacological target for hypocholesterolemia.
Is familial hypercholesterolemia a missense mutation?
A missense mutation in the low density lipoprotein receptor gene causes familial hypercholesterolemia in Sephardic Jews.
How do mutations increase PCSK9?
Mutations in the PCSK9 gene that disrupt the normal function of PCSK9 could therefore result in increased number of LDLRs and hypocholesterolemia. Also, the cholesterol-lowering effect of statins could be increased in subjects carrying mutations in the PCSK9 gene.
Which type of mutation of PCSK9 gene is cause familial hypercholesterolemia?
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics 34, 154–156, https://doi.org/10.1038/ng1161 (2003).
What are the most commonly reported adverse effects of PCSK9 inhibitors?
☑ RCTs assessing clinical effects of PCSK9 inhibitors alirocumab and evolocumab showed a favorable safety profile with a low rate of AEs. Most common reported AEs in RCTs are nasopharyngitis, upper respiratory tract infection, influenza‐like illness, myalgia, back pain, arthralgia, headache, and ISRs.
Where is PCSK9 is secreted?
PCSK9 is mainly expressed in adult liver, small intestine, kidneys,12,26 and pancreas. Although not expressed in adipocytes, circulating PCSK9 produced by the liver can regulate the levels of cell surface receptors in this tissue.
What are the genes that cause FH?
FH is caused by a mutation in one of three genes: the low-density lipoprotein cholesterol receptor (LDLR), Apolipoprotein B gene (APOB), or a gain-of-function mutation in the gene for proprotein convertase subtilisin/kexin type-9 (PCSK9).
Do PCSK9 inhibitors lower triglycerides?
Relative to LDL-C, PCSK9i reduce triglyceride concentrations to a much lesser extent compared to statins (LDL-C ≈ 18–55% and triglycerides ≈7–30% and up to 20–50% in hypertriglyceridemia) [54]. Similar to statins, the degree of triglyceride lowering correlates to pre-treatment triglyceride levels.
Are PCSK9 inhibitors monoclonal antibodies?
PCSK9 inhibitors: monoclonal antibodies for the treatment of hypercholesterolemia.
What is the effect of a missense mutation?
Missense mutations can affect DNA-transcription factors resulting in altering the expression of the corresponding protein. Altering the wild-type protein expression in the compartment where it is designed to function will disrupt the normal cell cycle and in turn may cause diseases [20].
What are the effects of PCSK9 mutations?
Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease (6). Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease (7–11).
How does PCSK9 cause hypercholesterolemia in mice?
Overexpression of PCSK9 in livers of mice markedly reduces hepatic LDL receptor (LDLR) protein (but not mRNA) levels, causing hypercholesterolemia (3). This finding suggested that the missense mutations identified by Abifadel et al. (1) conferred a gain-of-function to the mutant protein.
What is the prognosis of PCSK9 deficiency in young women?
Two young women with total PCSK9 deficiency have been identified (39). Both subjects had very low plasma levels of LDL-C (14 mg/dl and 16 mg/dl), providing perhaps the most compelling evidence of the importance of PCSK9 in LDL metabolism. No adverse clinical sequellae were reported in either individual.
What is the pathophysiology of proprotein convertase PCSK9?
The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem.2832363–2372. [PubMed] [Google Scholar]