URL of this page: https://medlineplus.gov/genetics/gene/lrp5/

LRP5 gene

LDL receptor related protein 5
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Normal Function

The LRP5 gene provides instructions for making a protein that is embedded in the outer membrane of many types of cells. It is known as a co-receptor because it works with another receptor protein, frizzled-4 (produced from the FZD4 gene), to transmit chemical signals from outside the cell to the cell's nucleus. Frizzled-4 and the LRP5 protein participate in the Wnt signaling pathway, a series of steps that affect the way cells and tissues develop. Wnt signaling is important for cell division (proliferation), attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities.

The LRP5 protein plays an important role in the development and maintenance of several tissues. During early development, it helps guide the specialization of cells in the retina, which is the light-sensitive tissue at the back of the eye. The LRP5 protein is also involved in establishing a blood supply to the retina and the inner ear. Additionally, this protein helps regulate bone mineral density, which is a measure of the amount of calcium and other minerals in bones. The minerals give the bones strength, making them less likely to break.

Health Conditions Related to Genetic Changes

Familial exudative vitreoretinopathy

More than 15 mutations in the LRP5 gene have been identified in people with the eye disease familial exudative vitreoretinopathy. Some of these mutations change single protein building blocks (amino acids) in the LRP5 protein, while others insert or delete genetic material in the gene. Most of these mutations reduce the amount of functional LRP5 protein that is produced within cells.

A reduction in the amount of LRP5 protein disrupts chemical signaling in the developing eye, which interferes with the formation of blood vessels at the edges of the retina. The resulting abnormal blood supply to this tissue can lead to retinal damage and vision loss. Because the LRP5 protein plays a role in bone formation, LRP5 gene mutations also cause reduced bone mineral density in some people with familial exudative vitreoretinopathy.

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Juvenile primary osteoporosis

At least five LRP5 gene mutations have been found in people with juvenile primary osteoporosis. Individuals with this condition have low bone mineral density and thinning of the bones (osteoporosis) beginning in childhood. Osteoporosis causes the bones to be brittle and to break easily, which leads to multiple bone fractures. The LRP5 gene mutations that cause this condition result in an LRP5 protein that is unable to transmit chemical signals along the Wnt signaling pathway. The resulting reduction in signaling disrupts regulation of bone mineral density, leading to osteoporosis at a young age.

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Osteoporosis-pseudoglioma syndrome

More than 40 LRP5 gene mutations that cause osteoporosis-pseudoglioma syndrome have been identified. Beginning in childhood, people with this condition have extremely low bone mineral density and osteoporosis, which leads to multiple bone fractures. Affected individuals also have eye abnormalities that cause vision impairment from birth or early infancy. Many LRP5 gene mutations that cause osteoporosis-pseudoglioma syndrome prevent cells from making any LRP5 protein. Other mutations change single amino acids in the LRP5 protein. These abnormal proteins cannot insert into the outer membrane of the cell, which makes them unable to perform their function. Loss of LRP5 protein function disrupts the chemical signaling pathways that are needed for the formation of bone and for normal retinal development, leading to the bone and eye abnormalities characteristic of osteoporosis-pseudoglioma syndrome. It is unclear why some LRP5 gene mutations affect eye development and others do not.

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Other disorders

Studies suggest that changes in the LRP5 gene may influence the risk of developing osteoporosis in adulthood. Other genetic and environmental factors likely contribute to this common disorder.

Other LRP5 gene mutations cause disorders associated with an increase in bone mineral density. These include autosomal dominant osteopetrosis type 1 and autosomal dominant osteosclerosis. In some cases, these conditions can cause abnormal bone growth and related skeletal abnormalities. Rarely, affected individuals have hearing loss or circulation problems in the brain. Other people with increased bone mineral density do not have any associated health problems. The mutations responsible for increased bone mineral density syndromes overactivate the LRP5 protein, which increases Wnt signaling within cells and enhances bone formation.

Other Names for This Gene

  • BMND1
  • EVR1
  • EVR4
  • HBM
  • low density lipoprotein receptor-related protein 5
  • low density lipoprotein receptor-related protein 7
  • LR3
  • LRP5_HUMAN
  • LRP7
  • OPS
  • OPTA1
  • VBCH2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Research Resources

References

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  • Balemans W, Van Hul W. The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology. 2007 Jun;148(6):2622-9. Epub 2007 Mar 29. Review. Citation on PubMed
  • Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002 May 16;346(20):1513-21. Citation on PubMed
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  • Hartikka H, Mäkitie O, Männikkö M, Doria AS, Daneman A, Cole WG, Ala-Kokko L, Sochett EB. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005 May;20(5):783-9. Epub 2005 Jan 4. Citation on PubMed
  • He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004 Apr;131(8):1663-77. Review. Citation on PubMed
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  • Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura KI. LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet. 2004;49(2):80-86. doi: 10.1007/s10038-003-0111-6. Epub 2004 Jan 15. Citation on PubMed
  • Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat. 2005 Aug;26(2):104-12. Citation on PubMed
  • Qin M, Kondo H, Tahira T, Hayashi K. Moderate reduction of Norrin signaling activity associated with the causative missense mutations identified in patients with familial exudative vitreoretinopathy. Hum Genet. 2008 Jan;122(6):615-23. Epub 2007 Oct 23. Citation on PubMed
  • Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Craig JE, Jiang L, Yang Z, Trembath R, Woodruff G, Gregory-Evans CY, Gregory-Evans K, Parker MJ, Black GC, Downey LM, Zhang K, Inglehearn CF. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004 Apr;74(4):721-30. Epub 2004 Mar 11. Citation on PubMed or Free article on PubMed Central
  • van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellström D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG; GENOMOS Study. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008 Mar 19;299(11):1277-90. doi: 10.1001/jama.299.11.1277. Citation on PubMed or Free article on PubMed Central
  • Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Bénichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003 Mar;72(3):763-71. Epub 2003 Feb 10. Citation on PubMed or Free article on PubMed Central
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