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LRP2
LDL receptor related protein 2
The LRP2 gene provides instructions for producing megalin, a receptor protein vital for transporting various molecules, including vitamins and hormones, in several organs. LRP2 encodes the megalin protein, which acts as a receptor in cells lining various body surfaces and cavities.
LRP2 is located on the long (q) arm of chromosome 2, at band 2q31.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The LRP2 gene is responsible for creating a protein known as megalin. Megalin functions as a receptor, meaning it has specific sites that bind to other proteins, called ligands, much like a key fits into a lock. This binding process initiates signals that are important for cell development and overall function throughout the body. Megalin is involved in a diverse range of bodily processes, including the absorption of essential vitamins A and D, immune system regulation, stress response, and the transport of fats in the bloodstream.
What the gene does
Megalin, the protein encoded by LRP2, is embedded within the membranes of epithelial cells, which line the body's internal and external surfaces. Its primary role involves moving its specific ligands from the cell surface into the cell, a process known as endocytosis. This receptor also facilitates the transport of ligands associated with cubilin, another related receptor protein. Megalin's activity is critical for the proper development and function of numerous physiological systems, including the central nervous system (brain and spinal cord), eyes, ears, lungs, intestines, reproductive system, and the renal tubules in the kidneys where urine is formed.
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Chromosome location
The LRP2 gene is situated on chromosome 2, specifically at position 2q31.1. This location indicates its placement on the long arm (q) of chromosome 2, within region 3, band 1, sub-band 1.
Protein structure
The LRP2 protein, megalin, is a large protein composed of 4655 amino acids. Its structure features multiple LDL-receptor class A domains, including LDL-receptor class A 1 (amino acids 27-63), LDL-receptor class A 2 (amino acids 66-104), LDL-receptor class A 3 (amino acids 107-143), LDL-receptor class A 4 (amino acids 146-180), LDL-receptor class A 5 (amino acids 182-218), LDL-receptor class A 6 (amino acids 221-257), and LDL-receptor class A 7 (amino acids 265-308). Additionally, it contains several LDL-receptor class B repeats, such as LDL-receptor class B 1 (amino acids 436-478), LDL-receptor class B 2 (amino acids 479-521), LDL-receptor class B 3 (amino acids 522-568), LDL-receptor class B 4 (amino acids 569-613), LDL-receptor class B 5 (amino acids 753-795), LDL-receptor class B 6 (amino acids 796-837), B 7 (amino acids 838-881), and B 8 (amino acids 882-925).
Key variants
Variants within the LRP2 gene can impact the function of the megalin protein. These genetic changes can lead to a range of effects, from altering protein production to affecting its ability to bind ligands or facilitate endocytosis. The clinical consequences of LRP2 variants can vary widely.
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.10589G>A | p.Trp3530Ter | Pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.10660C>T | p.Arg3554Ter | Pathogenic/Likely pathogenic | ★★☆☆ | LRP2-related disorder |
c.11323C>T | p.Arg3775Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.12136C>T | p.Arg4046Ter | Pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.12193C>T | p.Arg4065Ter | Pathogenic/Likely pathogenic | ★★☆☆ | LRP2-related disorder |
c.12316C>T | p.Arg4106Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.2647C>T | p.Arg883Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.3667+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.4741C>T | p.Arg1581Ter | Pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.4999C>T | p.Arg1667Ter | Pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
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 LRP2 gene are associated with Donnai-Barrow syndrome. This condition is believed to arise from the absence of functional megalin protein, particularly in the renal tubules. The lack of functional megalin can result in essential substances being excreted in the urine rather than being reabsorbed into the bloodstream. LRP2 variants have also been implicated in other conditions such as coloboma and certain aspects of prostate cancer progression. Some genetic variations in LRP2 have been linked to increased levels of low-density lipoproteins (LDLs) and cholesterol in the blood.
No disease links recorded for this gene in our reference set.
UK clinical status
The LRP2 gene is included in several expert-curated panels within the UK's NHS Genomic Medicine Service, as listed on PanelApp. These include panels for DDG2P (Developmental Disorders Genotype-to-Phenotype), Foetal anomalies (R21), Intellectual disability, Ocular coloboma, Retinal disorders (R32), and Structural eye disease (R36). This indicates its recognised clinical significance in diagnosing and managing these conditions within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LRP2 gene?
The LRP2 gene provides instructions for making megalin, a receptor protein that plays a crucial role in transporting various substances, including vitamins A and D, into cells from different body systems like the kidneys and brain.
Which conditions are associated with variants in the LRP2 gene?
Variants in the LRP2 gene are primarily associated with Donnai-Barrow syndrome. They have also been linked to conditions such as coloboma, certain aspects of prostate cancer, and elevated levels of LDLs and cholesterol.
Where is the LRP2 gene located?
The LRP2 gene is located on chromosome 2, specifically at position 2q31.1. This indicates its position on the long arm of chromosome 2.
References
- Kantarci S, Ragge NK, Thomas NS. Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. American journal of medical genetics. Part A. 2008. PMID: 18553518
- Holt SK, Karyadi DM, Kwon EM. Association of megalin genetic polymorphisms with prostate cancer risk and prognosis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008. PMID: 18559602
- Kantarci S, Al-Gazali L, Hill RS. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nature genetics. 2007. PMID: 17632512
- Christensen EI, Nielsen R. Role of megalin and cubilin in renal physiology and pathophysiology. Reviews of physiology, biochemistry and pharmacology. 2007. PMID: 17729440
- Mii A, Nakajima T, Fujita Y. Genetic association of low-density lipoprotein receptor-related protein 2 (LRP2) with plasma lipid levels. Journal of atherosclerosis and thrombosis. 2007. PMID: 18174661
- Fisher CE, Howie SE. The role of megalin (LRP-2/Gp330) during development. Developmental biology. 2006. PMID: 16828734
- Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nature reviews. Molecular cell biology. 2002. PMID: 11994745