Mechanisms of disease: genetic causes of familial hypercholesterolemia
Abstract
Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.
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Due to the critical role of LDLR in the metabolism of apoB-containing LDL particles in the circulation, strategies increasing the function and amount of LDLR protein in the liver have been extensively pursued as promising therapies for atherosclerosis and premature coronary heart disease.
“Due to the critical role of LDLR in the metabolism of apoB-containing LDL particles in the circulation, strategies increasing the function and amount of LDLR protein in the liver have been extensively pursued as promising therapies for atherosclerosis and premature coronary heart disease (Soutar and Naoumova, 2007).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Soutar and Naoumova, 2007
A couple of recently identified genes are known to regulate LDLR protein levels by affecting the trafficking and degradation of LDLR in peripheral tissues.
“A couple of recently identified genes are known to regulate LDLR protein levels by affecting the trafficking and degradation of LDLR in peripheral tissues (Soutar and Naoumova, 2007).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Soutar and Naoumova, 2007
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- Authors
- Soutar, A. K., & Naoumova, R. P.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Soutar, Anne K
- Venue
- Nature Clinical Practice Cardiovascular Medicine
- Published
- 2007-04
- Volume
- 4
- Issue
- 4
- Pages
- 214-225
- ISSN
- 1743-4297 (ISSN-L)
- 1743-4300
- OpenAlex
- W2114918865
- Cited by
- 608
- References
- 1
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 22 · 2023: 22 · 2022: 30 · 2021: 24 · 2020: 27 · 2019: 30 · 2018: 41 · 2017: 49 · 2016: 52 · 2015: 45 · 2014: 41 · 2013: 42 · 2012: 42
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Clinical Practice Cardiovascular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- familial hypercholesterolemia, LDL receptor, apolipoprotein B, LDLRAP1, PCSK9, loss-of-function mutations, gain-of-function mutations, atherosclerosis, coronary artery disease, gene dosage effect, LDL cholesterol lowering, PCSK9 inhibitors, statins
- MeSH terms
- Adult, Age Factors, Aged, Female, Gene Expression Regulation, Humans, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Male, Middle Aged, Prognosis, Receptors, LDL, Severity of Illness Index, Sex Factors, Incidence, Risk Assessment, Genetic Predisposition to Disease, Mutation, Missense, Apolipoprotein B-100
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