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LDLRAP1
low density lipoprotein receptor adaptor protein 1
The LDLRAP1 gene provides instructions for a protein critical in regulating cholesterol levels by facilitating the cellular uptake of low-density lipoproteins (LDL). The LDLRAP1 gene, also known as ARH, encodes a protein that is essential for removing cholesterol from the bloodstream.
LDLRAP1 is located on the short (p) arm of chromosome 1, at band 1p36.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The LDLRAP1 gene (low density lipoprotein receptor adaptor protein 1) is fundamental to cholesterol regulation within the human body. It provides the genetic blueprint for a protein that helps clear low-density lipoprotein (LDL) cholesterol from the blood, a process crucial for maintaining cardiovascular health. Abnormalities in this gene are associated with conditions that affect lipid metabolism.
What the gene does
The protein produced from the LDLRAP1 gene plays a vital role in cellular uptake of low-density lipoprotein (LDL) particles. This protein interacts with LDL receptors situated on the surface of cells, particularly liver cells. These receptors are responsible for binding to LDL particles circulating in the bloodstream. The LDLRAP1 protein then facilitates the transport of these receptor-LDL complexes from the cell surface into the cell's interior, a process known as endocytosis. Once inside the cell, LDLs are processed, releasing cholesterol for various cellular functions, storage, or elimination from the body. This mechanism is crucial for maintaining healthy cholesterol levels, especially within the liver, which largely manages the clearance of excess cholesterol.
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Chromosome location
The LDLRAP1 gene is located on the short arm of chromosome 1, specifically at position 1p36.11. This genomic location positions the gene within a region that is significant for its role in metabolic processes.
Protein structure
The LDLRAP1 protein consists of 308 amino acids and features several distinct functional regions. It contains a PID domain spanning amino acids 42-196, which is involved in protein-protein interactions. Further along the sequence, a Clathrin box motif is located at amino acids 212-216, essential for clathrin-mediated endocytosis. Additionally, an AP-2 complex binding region is found between amino acids 249-276, containing a specific [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif at amino acids 257-266, which is crucial for interaction with the AP-2 adaptor complex involved in vesicle formation.
Key variants
Genetic changes within the LDLRAP1 gene can disrupt the normal function of the encoded protein, leading to various health implications. These genetic alterations can impact the protein's ability to facilitate LDL uptake, thereby affecting cholesterol metabolism.
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 |
|---|---|---|---|---|
c.104G>A | p.Trp35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.113del | p.Thr38fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.143del | p.Phe48fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.226del | p.Ala76fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.344+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.402del | p.Ser135fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.439del | p.Leu147fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hypercholesterolemia, familial, 4 |
c.460-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | See cases |
c.466del | p.Ala156fs | Pathogenic | ★★☆☆ | Familial hypercholesterolemia |
c.604delinsCC | p.Ser202fs | Pathogenic | ★★☆☆ | Familial hypercholesterolemia |
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
Variants in the LDLRAP1 gene are primarily associated with a form of familial hypercholesterolaemia known as autosomal recessive hypercholesterolaemia. This condition is characterised by significantly elevated levels of LDL cholesterol in the blood, which can increase the risk of cardiovascular disease. More than 20 distinct genetic changes within the LDLRAP1 gene have been identified as causative for this condition. These changes typically result in the production of a non-functional or abnormally small LDLRAP1 protein, or they can prevent the production of the protein altogether.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic LDLRAP1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The LDLRAP1 gene is included in several NHS England Genomic Medicine Service approved panels. It is covered for Familial hypercholesterolaemia, including the GMS-specific R134 panel, and for conditions such as Likely inborn error of metabolism (R98) and Undiagnosed metabolic disorders, indicating its clinical relevance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a balanced diet and engaging in regular physical activity are generally recommended as part of a healthy lifestyle. Individuals concerned about cholesterol levels should discuss appropriate lifestyle management with a healthcare professional.
Supplement considerations
There is no conclusive evidence that dietary supplements can prevent or treat inherited forms of hypercholesterolaemia. Individuals should always consult their healthcare provider before considering any supplement, particularly if they have a genetic condition.
Frequently asked questions
What is the primary function of the LDLRAP1 gene?
The LDLRAP1 gene encodes a protein that helps cells, especially liver cells, take up low-density lipoprotein (LDL) cholesterol from the bloodstream. This process is vital for regulating overall cholesterol levels in the body.
What condition is associated with variants in the LDLRAP1 gene?
Variants in the LDLRAP1 gene are associated with autosomal recessive hypercholesterolaemia, a genetic disorder characterised by high levels of LDL cholesterol, which can increase the risk of cardiovascular disease.
How does LDLRAP1 contribute to cholesterol regulation?
LDLRAP1 facilitates the internalisation of LDL receptor-LDL complexes from the cell surface into the cell. This action allows LDLs to be broken down, removing cholesterol from circulation and preventing its accumulation in the blood.
References
- Sirinian MI, Belleudi F, Campagna F. Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes. The Journal of biological chemistry. 2005. PMID: 16129683
- Garuti R, Jones C, Li WP. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. The Journal of biological chemistry. 2005. PMID: 16179341
- Michaely P, Li WP, Anderson RG. The modular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits. The Journal of biological chemistry. 2004. PMID: 15166224
- Soutar AK, Naoumova RP. Autosomal recessive hypercholesterolemia. Seminars in vascular medicine. 2004. PMID: 15630633
- Soutar AK, Naoumova RP, Traub LM. Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arteriosclerosis, thrombosis, and vascular biology. 2003. PMID: 12958046
- Wilund KR, Yi M, Campagna F. Molecular mechanisms of autosomal recessive hypercholesterolemia. Human molecular genetics. 2002. PMID: 12417523
- Garcia CK, Wilund K, Arca M. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science (New York, N.Y.). 2001. PMID: 11326085