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LDLR
low density lipoprotein receptor
The LDLR gene codes for the low-density lipoprotein receptor, a protein vital for regulating cholesterol levels in the bloodstream and preventing its accumulation. The LDLR gene provides the blueprint for the low-density lipoprotein receptor protein.
LDLR is located on the short (p) arm of chromosome 19, at band 19p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The LDLR gene, or low-density lipoprotein receptor gene, is fundamental for maintaining healthy cholesterol levels within the human body. It provides instructions for synthesising a receptor protein that is crucial for the uptake of low-density lipoproteins (LDLs), often referred to as "bad" cholesterol, from the bloodstream into cells [PMID:17088191]. This process is essential for cells to acquire cholesterol for various biological functions, such as cell membrane formation and steroid hormone synthesis.
Dysfunction of the LDLR protein can lead to elevated levels of LDL cholesterol in the blood, a condition known as hypercholesterolaemia. Familial hypercholesterolaemia, an inherited disorder characterised by significantly high cholesterol from birth, is predominantly caused by pathogenic variants in the LDLR gene [PMID:33658514]. Understanding the LDLR gene's function is therefore key to comprehending the genetic basis of cholesterol metabolism and related health conditions.
What the gene does
The low-density lipoprotein receptor (LDLR) protein, encoded by the LDLR gene, acts as a cellular gateway for cholesterol-carrying low-density lipoproteins (LDLs). These receptors are located on the surface of many cell types, especially liver cells, where they bind to LDL particles circulating in the blood [PMID:17088191]. Once an LDL particle binds to the receptor, the receptor-LDL complex is internalised into the cell through a process called receptor-mediated endocytosis. Inside the cell, the LDL particle is transported to lysosomes, where it is broken down, releasing cholesterol for the cell's use or storage.
Following the delivery of its cargo, the LDLR protein is recycled back to the cell surface, ready to bind to more LDL particles. This continuous cycle is critical for regulating the amount of cholesterol in the bloodstream. A high density of LDLRs on liver cells, for instance, means more LDL cholesterol can be removed from circulation, thus lowering blood cholesterol levels [PMID:17088191]. Conversely, reduced function or absence of these receptors leads to LDL accumulation in the blood, contributing to conditions like familial hypercholesterolaemia.
The protein's intricate structure, including its various domains, facilitates this complex binding and internalisation process. The N-terminal ligand-binding domain, for example, is directly responsible for recognising and attaching to the apolipoprotein B-100 component found on LDL particles. The EGF precursor homology domain contributes to the receptor's release of LDL in endosomes, enabling its recycling. Without proper function of these domains, the uptake of LDL cholesterol is impaired, leading to its dangerous build-up in the body.
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Chromosome location
The LDLR gene is situated on chromosome 19, specifically at the cytogenetic location 19p13.2. This position refers to the short (p) arm of chromosome 19, within band 13.2. The gene spans approximately 45 kilobases and is composed of 18 exons, which are the coding regions of the gene that are ultimately translated into the LDLR protein. This genomic location is consistent across the human population and is critical for understanding its inheritance patterns and associations with genetic conditions.
Protein structure
The low-density lipoprotein receptor (LDLR) protein is composed of 860 amino acids and features a complex domain architecture essential for its function. The N-terminal region contains seven repeats of the LDL-receptor class A domain. These include LDL-receptor class A 1 (amino acids 25-65), LDL-receptor class A 2 (amino acids 66-106), LDL-receptor class A 3 (amino acids 107-145), LDL-receptor class A 4 (amino acids 146-186), LDL-receptor class A 5 (amino acids 195-233), LDL-receptor class A 6 (amino acids 234-272), and LDL-receptor class A 7 (amino acids 274-313). Notably, a region spanning amino acids 146-233 is involved in binding to Getah virus E1-E2 spike glycoproteins.
Following these class A domains are two EGF-like domains: EGF-like 1 (amino acids 314-353) and EGF-like 2; calcium-binding (amino acids 354-393). Further towards the C-terminus, the protein contains five LDL-receptor class B repeats: LDL-receptor class B 1 (amino acids 397-438), LDL-receptor class B 2 (amino acids 439-485), LDL-receptor class B 3 (amino acids 486-528), LDL-receptor class B 4 (amino acids 529-572), and LDL-receptor class B 5 (amino acids 573-615). This highly organised arrangement of domains facilitates the receptor's ability to bind to and internalise LDL particles, as well as its subsequent recycling to the cell surface.
Key variants
Variants within the LDLR gene can significantly impact the function of the low-density lipoprotein receptor, leading to impaired cholesterol metabolism. Over 2,000 different variants have been identified in this gene, ranging from small single nucleotide changes to larger deletions or insertions [PMID:33658514]. These genetic alterations can affect various aspects of the LDLR protein, including its production, its ability to bind LDL particles, or its capacity to be recycled back to the cell surface. Consequently, pathogenic LDLR variants are the most common cause of familial hypercholesterolaemia, an inherited condition characterised by dangerously high levels of LDL cholesterol from birth.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
g.(11089616_11100222)_(11107515_11110651)del | - | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
g.(?_11110652)_(11110771_?)del | - | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
g.(11218191_11221327)_(11224438_11225603)del | - | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.313+1G>A | - | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.1027G>A | p.Gly343Ser | Pathogenic | ★★★☆ | not provided |
c.1027G>T | p.Gly343Cys | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.1045C>T | p.Gln349Ter | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.1048C>T | p.Arg350Ter | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.1176C>A | p.Cys392Ter | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
c.1216C>T | p.Arg406Trp | Pathogenic | ★★★☆ | Hypercholesterolemia, familial, 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the LDLR gene are primarily associated with Familial hypercholesterolaemia (FH), an autosomal dominant inherited disorder. This condition is characterised by significantly elevated levels of low-density lipoprotein (LDL) cholesterol in the blood, leading to a substantially increased risk of early-onset cardiovascular disease, including heart attacks and strokes [PMID:33658514]. The severity of FH can vary depending on the specific variant and whether an individual inherits one (heterozygous FH) or two (homozygous FH) affected copies of the LDLR gene.
Inheritance pattern
Conditions caused by pathogenic LDLR variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The LDLR gene is recognised in the UK's NHS Genomic Medicine Service (GMS) pathways, reflecting its clinical significance. It is included on several green-rated PanelApp panels, indicating strong evidence for its association with disease and its use in clinical genetic testing. These panels include "Additional findings health related" for both adults and children, "Familial hypercholesterolaemia" (including the specific GMS R134 panel), "Likely inborn error of metabolism" (R98), and "Undiagnosed metabolic disorders". This comprehensive inclusion underscores the importance of LDLR gene testing in diagnosing and managing conditions related to cholesterol metabolism within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a heart-healthy lifestyle is often recommended for individuals with elevated cholesterol levels, though it cannot reverse the effects of genetic conditions like familial hypercholesterolaemia caused by LDLR variants. Research suggests that a balanced diet, low in saturated and trans fats, can contribute to overall cardiovascular health in the general population. Regular physical activity is also generally advised, as it can help improve lipid profiles and maintain a healthy weight [PMID:31252119]. Quitting smoking and moderating alcohol consumption are additional lifestyle modifications that can reduce the risk of cardiovascular disease. While these lifestyle changes are beneficial for everyone, they should be considered as complementary to, rather than a replacement for, medical management in individuals with genetically determined hypercholesterolaemia.
Supplement considerations
Several dietary supplements are sometimes promoted for cholesterol management, but there is no conclusive scientific evidence that they can prevent or cure conditions associated with LDLR gene variants or significantly lower genetically elevated cholesterol levels. Plant sterols and stanols, for instance, are known to modestly reduce LDL cholesterol absorption in the gut in some individuals [PMID:30604169]. Red yeast rice contains monacolins, which are structurally similar to statins, but its efficacy and safety are not consistently regulated. Omega-3 fatty acids from fish oil may help reduce triglyceride levels, but their impact on LDL cholesterol is less clear and can vary. It is crucial for individuals considering any supplement to discuss it with a healthcare professional, especially if they have a diagnosed condition or are taking prescription medications, to avoid potential interactions or adverse effects.
Frequently asked questions
What does the LDLR gene do?
The LDLR gene provides instructions for making the low-density lipoprotein receptor protein. This receptor removes low-density lipoprotein (LDL) cholesterol from the bloodstream, helping to regulate cholesterol levels.
What conditions are associated with LDLR gene variants?
Pathogenic variants in the LDLR gene are primarily associated with Familial hypercholesterolaemia (FH), an inherited condition characterised by very high levels of LDL cholesterol from birth.
How common are LDLR gene variants?
Pathogenic variants in the LDLR gene are the most common cause of Familial hypercholesterolaemia, affecting approximately 1 in 250 people in the general population. Over 2,000 different variants have been identified.
Can lifestyle changes help with conditions related to LDLR?
While lifestyle changes such as a heart-healthy diet and regular exercise are beneficial for overall cardiovascular health, they typically cannot fully compensate for the significant genetic predisposition to high cholesterol caused by pathogenic LDLR variants. Medical management is usually necessary.
Is the LDLR gene included in NHS genetic testing?
Yes, the LDLR gene is included on several NHS Genomic Medicine Service (GMS) PanelApp panels, including those for Familial hypercholesterolaemia and additional health-related findings, indicating its importance in clinical genetic testing in the UK.
What is the inheritance pattern for conditions linked to LDLR?
Conditions like Familial hypercholesterolaemia caused by LDLR gene variants typically follow an autosomal dominant inheritance pattern. This means only one copy of an altered gene in each cell is sufficient to cause the condition.
References
- Kong WJ, Liu J, Jiang JD. Human low-density lipoprotein receptor gene and its regulation. Journal of molecular medicine (Berlin, Germany). 2006. PMID: 16292665
- Jeon H, Blacklow SC. Structure and physiologic function of the low-density lipoprotein receptor. Annual review of biochemistry. 2005. PMID: 15952897
- Ueda M. Familial hypercholesterolemia. Molecular genetics and metabolism. 2005. PMID: 16421993
- Defesche JC. Low-density lipoprotein receptor--its structure, function, and mutations. Seminars in vascular medicine. 2004. PMID: 15199428
- van Aalst-Cohen ES, Jansen AC, de Jongh S. Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia. Seminars in vascular medicine. 2004. PMID: 15199431
- Marais AD, Firth JC, Blom DJ. Homozygous familial hypercholesterolemia and its management. Seminars in vascular medicine. 2004. PMID: 15199432
- Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science (New York, N.Y.). 2001. PMID: 11360986