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LDLRAP1
low density lipoprotein receptor adaptor protein 1
The LDLRAP1 gene provides instructions for a protein critical in removing low-density lipoprotein (LDL) cholesterol from the bloodstream, particularly important for liver function. The LDLRAP1 gene encodes the low density lipoprotein receptor adaptor protein 1, which facilitates the internalisation of LDL receptors bound to cholesterol-carrying LDL particles.
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, also known as ARH, provides instructions for creating a protein essential for managing cholesterol levels in the blood. This protein helps the liver, which is responsible for clearing most excess cholesterol, to efficiently remove low-density lipoprotein (LDL) particles. A disruption in this process can lead to higher-than-normal cholesterol levels.
Inherited changes in the LDLRAP1 gene are associated with autosomal recessive hypercholesterolaemia, a form of familial hypercholesterolaemia.
What the gene does
The LDLRAP1 protein plays a crucial role in the cellular uptake of low-density lipoprotein (LDL) cholesterol. It interacts with low-density lipoprotein receptors located on the surface of cells. These receptors bind to LDL particles, which are the primary transporters of cholesterol in the blood.
LDLRAP1 facilitates the movement of these LDL receptor-LDL complexes from the cell surface into the cell's interior. Once inside, the LDL particles are broken down, releasing cholesterol for cellular use, storage, or excretion from the body. This mechanism is vital for maintaining healthy cholesterol balance and preventing excessive accumulation in the bloodstream.
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Chromosome location
The LDLRAP1 gene is located on chromosome 1 at position 1p36.11. This region is found on the short (p) arm of chromosome 1, within band 36.11. The gene provides the genetic blueprint for a protein consisting of 308 amino acids.
Protein structure
The LDLRAP1 protein, which is 308 amino acids long, features several distinct functional regions. It contains a PID domain spanning amino acids 42-196, which is involved in binding to phosphoinositides. A Clathrin box motif is situated between amino acids 212-216, essential for clathrin-mediated endocytosis. Furthermore, an AP-2 complex binding region is found from 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 interacting with the AP-2 adaptor complex during receptor internalisation.
Key variants
Variants within the LDLRAP1 gene can impact the structure and function of the encoded protein. These genetic changes may lead to the production of an abnormally short or non-functional protein, or they might prevent the protein from being produced at all. Such alterations can impair the cell's ability to clear LDL cholesterol from the bloodstream.
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 | ★★☆☆ | Hypercholesterolemia, familial, 4 |
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 autosomal recessive hypercholesterolaemia, a specific form of familial hypercholesterolaemia. This condition is characterised by elevated levels of LDL cholesterol in the blood, which can increase the risk of cardiovascular disease. The inability of cells to effectively remove LDL due to impaired LDLRAP1 protein function underlies the development of this disorder.
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
LDLRAP1 is included in several UK NHS Genomic Medicine Service (GMS) panels. It is part of the 'Familial hypercholesterolaemia' panel and the 'Familial hypercholesterolaemia (GMS)' panel (R134). Additionally, it is listed on the 'Likely inborn error of metabolism' panel (R98) and the 'Undiagnosed metabolic disorders' panel, reflecting its role in metabolic health.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LDLRAP1 protein?
The LDLRAP1 protein helps remove cholesterol from the bloodstream by facilitating the internalisation of low-density lipoprotein (LDL) receptors bound to cholesterol-carrying LDL particles into cells, particularly in the liver.
Which condition is associated with variants in the LDLRAP1 gene?
Variants in the LDLRAP1 gene are associated with autosomal recessive hypercholesterolaemia, a form of familial hypercholesterolaemia characterised by high levels of LDL cholesterol.
How does LDLRAP1 contribute to cholesterol regulation?
LDLRAP1 helps move LDL receptor-LDL complexes from the cell surface into the cell's interior. This process allows the breakdown of LDL and the release of cholesterol, which is then used, stored, or removed from the body, thus regulating blood cholesterol levels.
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