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LRP2
LDL receptor related protein 2
The LRP2 gene provides instructions for producing megalin, a receptor protein that plays a vital role in cellular transport and the absorption of essential substances in the body. LRP2 encodes the megalin protein, which functions as a receptor to bind and internalise various molecules from the cell surface.
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, also known as low-density lipoprotein receptor-related protein 2, provides the genetic blueprint for a protein called megalin. Megalin acts as a receptor, facilitating the uptake of various molecules, or ligands, into cells. This process is crucial for a wide array of physiological functions across different organ systems within the body.
What the gene does
The megalin protein, encoded by the LRP2 gene, functions primarily as a receptor involved in endocytosis, a process where cells absorb external materials by engulfing them. Megalin binds to numerous ligands, acting like a 'key-and-lock' mechanism to initiate signals affecting cell development and function. Its diverse roles include the absorption of vital nutrients such as vitamins A and D, contributing to immune responses, regulating stress pathways, and facilitating lipid transport in the bloodstream. Megalin is embedded within the membranes of epithelial cells, which line many body surfaces and cavities. It is also involved in transporting ligands for another related receptor, cubulin, highlighting its central role in cellular uptake mechanisms. Megalin is critical for the proper development and function of several organs, including the brain, spinal cord, eyes, ears, lungs, intestines, reproductive system, and the renal tubules in the kidneys.
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Chromosome location
The LRP2 gene is situated on chromosome 2, specifically at position 2q31.1. This location refers to the long (q) arm of chromosome 2, in region 3, band 1, sub-band 1.
Protein structure
The LRP2 gene encodes a large protein of 4655 amino acids. Its structure includes multiple LDL-receptor class A domains and LDL-receptor class B repeats. Specifically, there are seven LDL-receptor class A domains: 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). The protein also contains eight LDL-receptor class B repeats: 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), LDL-receptor class B 7 (amino acids 838-881), and LDL-receptor class B 8 (amino acids 882-925).
Key variants
Variants within the LRP2 gene can alter the structure or function of the megalin protein, impacting its ability to bind and transport various ligands. These genetic changes can range from single nucleotide alterations to larger deletions or insertions, potentially leading to a non-functional or absent megalin protein.
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.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.3667+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.5857C>T | p.Arg1953Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.6283C>T | p.Arg2095Ter | Pathogenic/Likely pathogenic | ★★☆☆ | LRP2-related disorder |
c.6673C>T | p.Arg2225Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.697C>T | p.Arg233Ter | Pathogenic | ★★☆☆ | Fetal anomalies with a likely genetic cause |
c.832C>T | p.Arg278Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Donnai-Barrow syndrome |
c.9550C>T | p.Arg3184Ter | Pathogenic/Likely 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, a rare genetic disorder. This syndrome arises when the megalin protein is non-functional or absent, particularly impacting its role in the renal tubules. This dysfunction results in the excretion of megalin's ligands in the urine, which would normally be reabsorbed into the bloodstream. LRP2 variants are also associated with coloboma. Additionally, some LRP2 polymorphisms have been linked to elevated levels of low-density lipoproteins (LDLs) and cholesterol, while others may be associated with prostate cancer progression.
No disease links recorded for this gene in our reference set.
UK clinical status
The LRP2 gene is included on several NHS Genomic Medicine Service national panels for various conditions. It is part of the DDG2P (green), Foetal anomalies (green, R21), Intellectual disability (green), Ocular coloboma (green), Retinal disorders (green, R32), and Structural eye disease (green, R36) panels, indicating its clinical relevance in 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 the megalin protein, a receptor crucial for internalising various molecules into cells. It plays key roles in vitamin absorption, immune function, and lipid transport, especially in the kidneys and other organs.
Which condition is strongly associated with LRP2 gene variants?
Variants in the LRP2 gene are strongly associated with Donnai-Barrow syndrome. This condition occurs due to a lack of functional megalin, leading to specific developmental and physiological challenges.
How does megalin affect kidney function?
In the kidneys, megalin is active in the renal tubules, where it helps reabsorb various ligands that would otherwise be excreted in urine. Dysfunction of megalin in this area can lead to the loss of essential substances from the body.
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