The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream.
Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis), and is also involved in transporting the ligands of a related receptor called cubulin. Megalin is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules).
Health Conditions Related to Genetic Changes
At least twelve LRP2 gene mutations have been identified in people with Donnai-Barrow syndrome. These mutations are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein. However, it is unclear how these abnormalities result in the specific signs and symptoms of the disorder.
A condition previously classified as a separate disorder called facio-oculo-acoustico-renal (FOAR) syndrome has also been found to be caused by LRP2 gene mutations. FOAR syndrome is now considered to be the same disorder as Donnai-Barrow syndrome.More About This Health Condition
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Certain LRP2 gene polymorphisms have also been associated with increased levels of low-density lipoproteins (LDLs) and cholesterol in the blood. LDLs are the primary carriers of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. Increased LDL levels may result in excess cholesterol circulating through the bloodstream and accumulating on the walls of the blood vessels, increasing a person's risk of cardiovascular disease.
LDLs are among megalin's ligands, and researchers believe that variations in megalin function resulting from LRP2 gene changes may influence LDL levels.
Certain common genetic variations (polymorphisms) in the LRP2 gene may be associated with differences in the progression, recurrence, and severity of prostate cancer in affected men. Androgens, which are male sex hormones that contribute to the growth of cancerous (malignant) prostate tumors, are among megalin's ligands. A recent study suggests that prostate tumor cells may produce increased amounts of megalin and thereby absorb more androgens. LRP2 gene polymorphisms that increase the activity of megalin may encourage more aggressive tumor growth, while polymorphisms that decrease the activity of megalin may tend to slow tumor growth.
Other Names for This Gene
- calcium sensor protein
- glycoprotein 330 (gp330)
- Heymann nephritis antigen homolog
- low density lipoprotein receptor-related protein 2
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol. 2002 Apr;3(4):256-66. Review. Citation on PubMed
- Christensen EI, Nielsen R. Role of megalin and cubilin in renal physiology and pathophysiology. Rev Physiol Biochem Pharmacol. 2007;158:1-22. Citation on PubMed
- Fisher CE, Howie SE. The role of megalin (LRP-2/Gp330) during development. Dev Biol. 2006 Aug 15;296(2):279-97. Epub 2006 Jun 8. Review. Citation on PubMed
- Holt SK, Karyadi DM, Kwon EM, Stanford JL, Nelson PS, Ostrander EA. Association of megalin genetic polymorphisms with prostate cancer risk and prognosis. Clin Cancer Res. 2008 Jun 15;14(12):3823-31. doi: 10.1158/1078-0432.CCR-07-4566. Citation on PubMed or Free article on PubMed Central
- Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, MacLaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet. 2007 Aug;39(8):957-9. Epub 2007 Jul 15. Citation on PubMed or Free article on PubMed Central
- Kantarci S, Ragge NK, Thomas NS, Robinson DO, Noonan KM, Russell MK, Donnai D, Raymond FL, Walsh CA, Donahoe PK, Pober BR. Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. Am J Med Genet A. 2008 Jul 15;146A(14):1842-7. doi: 10.1002/ajmg.a.32381. Citation on PubMed or Free article on PubMed Central
- Mii A, Nakajima T, Fujita Y, Iino Y, Kamimura K, Bujo H, Saito Y, Emi M, Katayama Y. Genetic association of low-density lipoprotein receptor-related protein 2 (LRP2) with plasma lipid levels. J Atheroscler Thromb. 2007 Dec;14(6):310-6. Epub 2007 Dec 17. Citation on PubMed