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LRP5  -  low density lipoprotein receptor-related...

Homo sapiens

 
 
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Disease relevance of LRP5

  • The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait [1].
  • Therefore, our patient's extensive oropharyngeal exostoses and endosteal hyperostosis likely reflect increased Wnt signaling and show that exuberant LRP5 effects are not always benign [2].
  • We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants [3].
  • Our previous work using clinical OS samples suggested that expression of the Wnt receptor LRP5 might be associated with tumor metastasis [4].
  • SUMMARY: Identification of pathogenic mutations and allelic variations in LRP5 has improved our understanding of the physiology of bone mass acquisition and the pathophysiology of several bone diseases, including osteoporosis [5].
 

Psychiatry related information on LRP5

  • We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD [6].
 

High impact information on LRP5

  • Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity [7].
  • We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway [8].
  • LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt [9].
  • Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass [10].
  • We sequenced the coding exons of LRP5 in 37 probands suspected of having OPPG on the basis of the co-occurrence of severe congenital or childhood-onset visual impairment with bone fragility or osteoporosis recognized by young adulthood [11].
 

Chemical compound and disease context of LRP5

 

Biological context of LRP5

  • Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q [14].
  • We expressed seven different HBM-LRP5 missense mutations to delineate the mechanism by which they alter Wnt signaling [15].
  • INTRODUCTION: Gain-of-function mutation (Gly171Val) of LDL receptor-related protein 5 (LRP5) was discovered in 2002 in two American kindreds with high bone mass and benign phenotypes [2].
  • Indeed, LRP5 is now known to play a particularly important role in bone formation such that the loss of this component results in a reduction in osteoblast number, a delay in mineralization, and a reduction in peak bone mineral density [16].
  • PCR amplification and sequencing of LRP5 exons 2-4 and adjacent splice sites revealed heterozygosity for a new LRP5 missense mutation, Arg154Met [2].
 

Anatomical context of LRP5

 

Associations of LRP5 with chemical compounds

 

Physical interactions of LRP5

  • LDLR-deficient cells transduced by recombinant adenovirus containing human LRP5 exhibited increased binding of apolipoprotein E (apoE)-enriched beta-migrating very low density lipoprotein [19].
  • The G171V mutation prevents Dkk from binding to LRP5, thereby increasing LRP5 function; the result is high bone mass due to uncoupling of bone formation and resorption [24].
  • During the course of a VDR ChIP-chip analysis we found that 1,25(OH)(2)D(3) could induce binding of the VDR to sites within the Lrp5 gene locus [25].
 

Regulatory relationships of LRP5

  • Canonical WNT signals are transduced through Frizzled receptor and LRP5/6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser 9 phosphorylation [26].
  • In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes [6].
  • In addition, Dkk-3 and dominant-negative LRP5 also induce changes in beta-catenin localization consistent with an increase in cell-cell adhesion [4].
 

Other interactions of LRP5

  • Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling [15].
  • SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor [27].
  • Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene [1].
  • Here, we present our refined linkage curve of the IDDM4 region, comprising 32 microsatellite markers and 12 SNPs, providing a peak MLS=2.58, P=5 x 10(-4), at LRP5 g.17646G>T [28].
  • Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family [29].
 

Analytical, diagnostic and therapeutic context of LRP5

  • MATERIALS AND METHODS: We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects [30].
  • Epitope tagged cell supernatants containing either Sost or soluble mutant or wildtype LRP5/LRP6 were used for immunoprecipitation [31].
  • Sequencing of exon 3 of LRP5 in 10 OS patient-derived cell cultures showed no activating mutation of LRP5 [32].
  • In addition, RT-PCR for LRP5 expression was performed in 44 OS patient samples and the findings were correlated with clinical data [32].
  • In addition, patients whose tumors were positive for LRP5 showed a trend toward decreased event-free survival (p = 0.066) [32].

References

  1. Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13. Van Hul, E., Gram, J., Bollerslev, J., Van Wesenbeeck, L., Mathysen, D., Andersen, P.E., Vanhoenacker, F., Van Hul, W. J. Bone Miner. Res. (2002) [Pubmed]
  2. Oropharyngeal skeletal disease accompanying high bone mass and novel LRP5 mutation. Rickels, M.R., Zhang, X., Mumm, S., Whyte, M.P. J. Bone Miner. Res. (2005) [Pubmed]
  3. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Van Wesenbeeck, L., Cleiren, E., Gram, J., Beals, R.K., Bénichou, O., Scopelliti, D., Key, L., Renton, T., Bartels, C., Gong, Y., Warman, M.L., De Vernejoul, M.C., Bollerslev, J., Van Hul, W. Am. J. Hum. Genet. (2003) [Pubmed]
  4. Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Hoang, B.H., Kubo, T., Healey, J.H., Yang, R., Nathan, S.S., Kolb, E.A., Mazza, B., Meyers, P.A., Gorlick, R. Cancer Res. (2004) [Pubmed]
  5. Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass. Ferrari, S.L., Deutsch, S., Antonarakis, S.E. Curr. Opin. Lipidol. (2005) [Pubmed]
  6. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Kiel, D.P., Ferrari, S.L., Cupples, L.A., Karasik, D., Manen, D., Imamovic, A., Herbert, A.G., Dupuis, J. Bone (2007) [Pubmed]
  7. Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Hsieh, J.C., Lee, L., Zhang, L., Wefer, S., Brown, K., DeRossi, C., Wines, M.E., Rosenquist, T., Holdener, B.C. Cell (2003) [Pubmed]
  8. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Gong, Y., Slee, R.B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A.M., Wang, H., Cundy, T., Glorieux, F.H., Lev, D., Zacharin, M., Oexle, K., Marcelino, J., Suwairi, W., Heeger, S., Sabatakos, G., Apte, S., Adkins, W.N., Allgrove, J., Arslan-Kirchner, M., Batch, J.A., Beighton, P., Black, G.C., Boles, R.G., Boon, L.M., Borrone, C., Brunner, H.G., Carle, G.F., Dallapiccola, B., De Paepe, A., Floege, B., Halfhide, M.L., Hall, B., Hennekam, R.C., Hirose, T., Jans, A., Jüppner, H., Kim, C.A., Keppler-Noreuil, K., Kohlschuetter, A., LaCombe, D., Lambert, M., Lemyre, E., Letteboer, T., Peltonen, L., Ramesar, R.S., Romanengo, M., Somer, H., Steichen-Gersdorf, E., Steinmann, B., Sullivan, B., Superti-Furga, A., Swoboda, W., van den Boogaard, M.J., Van Hul, W., Vikkula, M., Votruba, M., Zabel, B., Garcia, T., Baron, R., Olsen, B.R., Warman, M.L. Cell (2001) [Pubmed]
  9. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mao, J., Wang, J., Liu, B., Pan, W., Farr, G.H., Flynn, C., Yuan, H., Takada, S., Kimelman, D., Li, L., Wu, D. Mol. Cell (2001) [Pubmed]
  10. Regulation of bone mass by Wnt signaling. Krishnan, V., Bryant, H.U., Macdougald, O.A. J. Clin. Invest. (2006) [Pubmed]
  11. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Ai, M., Heeger, S., Bartels, C.F., Schelling, D.K. Am. J. Hum. Genet. (2005) [Pubmed]
  12. Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. Guo, Y.F., Xiong, D.H., Shen, H., Zhao, L.J., Xiao, P., Guo, Y., Wang, W., Yang, T.L., Recker, R.R., Deng, H.W. J. Med. Genet. (2006) [Pubmed]
  13. Interactions between the unicellular red alga Rhodella reticulata (Rhodophyta) and contaminated bacteria. Toncheva-Panova, T.G., Ivanova, J.G. J. Appl. Microbiol. (2002) [Pubmed]
  14. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Toomes, C., Bottomley, H.M., Jackson, R.M., Towns, K.V., Scott, S., Mackey, D.A., Craig, J.E., Jiang, L., Yang, Z., Trembath, R., Woodruff, G., Gregory-Evans, C.Y., Gregory-Evans, K., Parker, M.J., Black, G.C., Downey, L.M., Zhang, K., Inglehearn, C.F. Am. J. Hum. Genet. (2004) [Pubmed]
  15. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Ai, M., Holmen, S.L., Van Hul, W., Williams, B.O., Warman, M.L. Mol. Cell. Biol. (2005) [Pubmed]
  16. 1,25-Dihydroxyvitamin D3 regulates the expression of low-density lipoprotein receptor-related protein 5 via deoxyribonucleic acid sequence elements located downstream of the start site of transcription. Fretz, J.A., Zella, L.A., Kim, S., Shevde, N.K., Pike, J.W. Mol. Endocrinol. (2006) [Pubmed]
  17. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Little, R.D., Carulli, J.P., Del Mastro, R.G., Dupuis, J., Osborne, M., Folz, C., Manning, S.P., Swain, P.M., Zhao, S.C., Eustace, B., Lappe, M.M., Spitzer, L., Zweier, S., Braunschweiger, K., Benchekroun, Y., Hu, X., Adair, R., Chee, L., FitzGerald, M.G., Tulig, C., Caruso, A., Tzellas, N., Bawa, A., Franklin, B., McGuire, S., Nogues, X., Gong, G., Allen, K.M., Anisowicz, A., Morales, A.J., Lomedico, P.T., Recker, S.M., Van Eerdewegh, P., Recker, R.R., Johnson, M.L. Am. J. Hum. Genet. (2002) [Pubmed]
  18. Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25). Veltman, I.M., Vreede, L.A., Cheng, J., Looijenga, L.H., Janssen, B., Schoenmakers, E.F., Yeh, E.T., van Kessel, A.G. Hum. Mol. Genet. (2005) [Pubmed]
  19. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. Kim, D.H., Inagaki, Y., Suzuki, T., Ioka, R.X., Yoshioka, S.Z., Magoori, K., Kang, M.J., Cho, Y., Nakano, A.Z., Liu, Q., Fujino, T., Suzuki, H., Sasano, H., Yamamoto, T.T. J. Biochem. (1998) [Pubmed]
  20. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Ohnaka, K., Taniguchi, H., Kawate, H., Nawata, H., Takayanagi, R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  21. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Fujino, T., Asaba, H., Kang, M.J., Ikeda, Y., Sone, H., Takada, S., Kim, D.H., Ioka, R.X., Ono, M., Tomoyori, H., Okubo, M., Murase, T., Kamataki, A., Yamamoto, J., Magoori, K., Takahashi, S., Miyamoto, Y., Oishi, H., Nose, M., Okazaki, M., Usui, S., Imaizumi, K., Yanagisawa, M., Sakai, J., Yamamoto, T.T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  22. Expression of the type I diabetes-associated gene LRP5 in macrophages, vitamin A system cells, and the Islets of Langerhans suggests multiple potential roles in diabetes. Figueroa, D.J., Hess, J.F., Ky, B., Brown, S.D., Sandig, V., Hermanowski-Vosatka, A., Twells, R.C., Todd, J.A., Austin, C.P. J. Histochem. Cytochem. (2000) [Pubmed]
  23. Bile salt-stimulated lipase and digestion of non-breast milk fat. McClean, P., Harding, M., Coward, W.A., Prentice, A., Austin, S., Weaver, L.T. J. Pediatr. Gastroenterol. Nutr. (1998) [Pubmed]
  24. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Levasseur, R., Lacombe, D., de Vernejoul, M.C. Joint, bone, spine : revue du rhumatisme. (2005) [Pubmed]
  25. 1,25-Dihydroxyvitamin D(3) induces expression of the Wnt signaling co-regulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. Fretz, J.A., Zella, L.A., Kim, S., Shevde, N.K., Pike, J.W. J. Steroid Biochem. Mol. Biol. (2007) [Pubmed]
  26. Cross-talk of WNT and FGF Signaling Pathways at GSK3beta to Regulate beta-Catenin and SNAIL Signaling Cascades. Katoh, M., Katoh, M. Cancer Biol. Ther. (2006) [Pubmed]
  27. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. Semënov, M., Tamai, K., He, X. J. Biol. Chem. (2005) [Pubmed]
  28. Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Twells, R.C., Mein, C.A., Payne, F., Veijola, R., Gilbey, M., Bright, M., Timms, A., Nakagawa, Y., Snook, H., Nutland, S., Rance, H.E., Carr, P., Dudbridge, F., Cordell, H.J., Cooper, J., Tuomilehto-Wolf, E., Tuomilehto, J., Phillips, M., Metzker, M., Hess, J.F., Todd, J.A. Hum. Genet. (2003) [Pubmed]
  29. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. Brown, S.D., Twells, R.C., Hey, P.J., Cox, R.D., Levy, E.R., Soderman, A.R., Metzker, M.L., Caskey, C.T., Todd, J.A., Hess, J.F. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  30. Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. van Meurs, J.B., Rivadeneira, F., Jhamai, M., Hugens, W., Hofman, A., van Leeuwen, J.P., Pols, H.A., Uitterlinden, A.G. J. Bone Miner. Res. (2006) [Pubmed]
  31. Bone Density Ligand, Sclerostin, Directly Interacts With LRP5 but Not LRP5(G171V) to Modulate Wnt Activity. Ellies, D.L., Viviano, B., McCarthy, J., Rey, J.P., Itasaki, N., Saunders, S., Krumlauf, R. J. Bone Miner. Res. (2006) [Pubmed]
  32. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Hoang, B.H., Kubo, T., Healey, J.H., Sowers, R., Mazza, B., Yang, R., Huvos, A.G., Meyers, P.A., Gorlick, R. Int. J. Cancer (2004) [Pubmed]
 
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