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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review LRP5 (low density lipoprotein receptor-related protein 5) Zhendong Alex Zhong, Bart O Williams Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan 49503-2518, USA (ZAZ, BOW) Published in Atlas Database: June 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/LRP5ID44282ch11q13.html DOI: 10.4267/2042/44982 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Protein Other names: BMND1, EVR1, EVR4, HBM, LR3, LRP7, OPPG, OPS, OPTA1, VBCH2 HGNC (Hugo): LRP5 Location: 11q13.2 Description LRP5 contains a large extracellular domain (ECD) making up over 85% of the approximately 1600-aminoacid protein. At the amino terminus of the ECD, four beta-propeller motifs and four epidermal growth factor (EGF)-like repeats create the binding sites for extracellular ligands. These domains are followed by three LDLR type A (LA) domains. The intracellular domain of LRP5 contains 5 PPPSP motifs, to which Axin preferentially binds after phosphorylation of the PPPSP motif induced by Wnt ligands. Tamai et al. showed that Wnt activates LRP5's homologue, LRP6, by inducing LRP6 phosphorylation at the PPP(S/T)P motifs, which serve as inducible docking sites for Axin, thereby recruiting Axin to the plasma membrane. DNA/RNA Description Genomic size: 136636; genomic sequence: (chr11: 67 836 684-67 973 319). Transcription 5161 bp mRNA; (NM_002335, 05-oct-2009). Pseudogene Homo sapiens low density lipoprotein receptor-related protein 5-like (LRP5L), transcript variant 1, Aliases: DKFZp434O0213, NCBI Reference Sequence: NM_182492.2, Location: 22q11.23, HGNC ID: HGNC:25323. Expression Widely expressed, with the highest level of expression in the liver. Exon count: 23; coding exon count: 23. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 270 LRP5 (low density lipoprotein receptor-related protein 5) Zhong ZA, Williams BO Mutations Germinal The heterozygous LRP5V171 mutation cosegregated with high bone density. This gain-of-function mutation in LRP5 causes an autosomal dominant disorder characterized by high bone density, torus palatinus, and a wide, deep mandible. In 2001, Gong et al. reported that they identified a total of six different homozygous frame-shift or nonsense mutations in affected offspring from consanguineous families affected by osteoporosis pseudoglioma syndrome. They also found homozygous missense mutations in affected patients from two other consanguineous families and heterozygous nonsense, frame-shift, and missense mutations in affected patients from four nonconsanguineous families. Many patients with this syndrome are also born with severe disruption of the ocular structure, phthisis bulbi. Jiao et al. reported that homozygous mutations R570Q, R752G, and E1367K in LRP5 cosegregated with familial exudative vitreoretinopathy (FEVR). There are many other papers reporting LRP5 gene mutations and SNP polymorphisms that are associated with bone density variation, familial exudative vitreoretinopathy, obesity, etc. Schematic diagram of human LRP5, 1615 aa. (from He et al., Development. 2004 Apr;131(8):1663-77). Post-translational modification: Phosphorylation of the PPPSP motif creates an inducible docking site for Axin. Palmitoylation is required for LRP6 to exit the endoplasmic reticulum (ER). Somatic Westin's group reported that the tumor-associated shorter transcript of LRP5 containing an in-frame deletion of 142 amino acids (D666-809) was strongly implicated in deregulated activation of the Wnt/betacatenin signaling pathway in hyperparathyroid tumors and mammary gland tumorigenesis. Localisation Membrane; single-pass type I membrane protein. Function Involved in the Wnt/beta catenin signaling pathway, acting as a co-receptor together with Frizzled for Wnt ligands. Schematic representation of LRP5 mutations; those associated with osteoporosis pseudoglioma (OPPG) syndrome, autosomal-dominant familial exudative vitreoretinopathy (FEVR), and various high-bone-density diseases are shown in red, purple, and green, respectively. Arrows indicate mutation locations: *, nonsense mutation; fs, frame-shift mutation. (from He et al., Development. 2004 Apr;131(8):166377). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 271 LRP5 (low density lipoprotein receptor-related protein 5) Zhong ZA, Williams BO Cytogenetics Gong et al. found that OPPG carriers have reduced bone mass when compared with age- and gendermatched controls. They demonstrated LRP5 expression by osteoblasts in situ and showed that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. They also showed that a mutant secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass. Ai et al. 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 and bone fragility or osteoporosis recognized by young adulthood. They measured the ability of wild-type and mutant LRP5 to transduce Wnt and Norrin signals ex vivo. Each of the seven OPPG mutations tested had reduced signal transduction relative to wild-type controls. These results indicate that early bilateral vitreoretinal eye pathology coupled with skeletal fragility is a strong predictor of LRP5 mutation and that mutations in LRP5 cause OPPG by impairing Wnt and Norrin signal transduction. In 2008, Yadav et al. identified Tph1, which encodes the rate-limiting enzyme in serotonin synthesis, as the most highly overexpressed gene in LRP5-/- mice. Tph1 expression was also elevated in LRP5-/- duodenal cells. Decreasing serotonin blood levels normalized bone formation and bone mass in LRP5-/- mice, and gutspecific LRP5 inactivation decreased bone formation in a beta-catenin-independent manner. They concluded that LRP5 inhibits bone formation by inhibiting serotonin production in the gut. Cheung et al. identified a family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene (W478R and W504C). In 2007, Drenser et al. found familial exudative vitreoretinopathy and osteoporosis pseudoglioma syndrome caused by a mutation in the LRP5 gene. Xiong et al. found that LRP5 gene polymorphisms are associated with bone mass density in both Chinese and whites. The Chinese sample consisted of 733 unrelated subjects and the white sample was made up of 1873 subjects from 405 nuclear families. The most frequently studied polymorphisms in LRP5 are two amino acid substitutions, Val667Met and Ala1330Val. A common variant of LRP6, Ile1062Val, contributes to fracture risk in elderly men, and is linked to coronary heart disease and low BMD. In 2008, Joyce et al. confirmed that the two common LRP5 variants are consistently associated with BMD and fracture risk across different white populations, but the LRP6 variant is not. Implicated in Hyperparathyroid tumors, breast cancer Note According to Bjorklund's reports, the internally truncated human LRP5 receptor is strongly implicated in deregulated activation of the Wnt/beta-catenin signaling pathway in hyperparathyroid tumors and mammary gland tumorigenesis, and thus presents a potential target for therapeutic intervention. The truncation version of LRP5 (LRP5∆666-809) missed the last 93 bp of exon 9, all 227 bp of exon 10, and the first 106 bp of exon 11. Oncogenesis Reverse transcription PCR and Western blot analysis showed expression of truncated LRP5 in 32 out of 37 primary hyperparathyroidism (pHPT) tumors (86%) and 20 out of 20 secondary hyperparathyroidism (SHPT) tumors (100%). Truncated LRP5 frequently expressed in breast tumors of different cancer stages (58-100%), including carcinoma in situ and metastatic carcinoma. Truncated LRP5 was required in MCF7 breast cancer cells for the nonphosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. Other cancers Note LRP5 is required for maintaining the basal lineage of mouse mammary tissue (Badders et al., 2009) and for mammary ductal stem cell activity and Wnt1-induced tumorigenesis (Lindvall et al., 2006). LRP5 is a novel marker for disease progression in highgrade osteosarcoma (Hoang et al., 2004). Dominant negative LRP5 showed inhibition of osteosarcoma tumorigenicity and metastasis in mouse model (Guo et al., 2008). Osteoporosis-pseudoglioma syndrome (OPPG) Note Children with the autosomal recessive disorder osteoporosis pseudoglioma syndrome (OPPG) (Gong et al., 1996) have very low bone mass and are prone to developing fractures and deformation. In addition to the skeletal phenotype, many individuals with OPPG have eye involvement in the form of severe disruption of the ocular structure, called phthisis bulbi. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 272 LRP5 (low density lipoprotein receptor-related protein 5) Zhong ZA, Williams BO reducing the number of targets for paracrine DKK1 to antagonize without affecting the activity of autocrine Wnt. Ai et al. expressed seven different HBM-LRP5 missense mutations, including G171V, to delineate the mechanism by which they alter Wnt signaling. Each mutant receptor was able to reach the cell surface, albeit in differing amounts, and transduce exogenously supplied Wnt1 and Wnt3a signals. The affinities between the mutant forms of LRP5 and Mesd did not correlate with their abilities to reach the cell surface. All HBM mutant proteins had reduced physical interaction with and reduced inhibition by DKK1. These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations' physiologic effects is via reduced affinity to and inhibition by DKK1. Semenov further showed that LRP5 HBM mutant proteins exhibit reduced binding to a secreted bonespecific LRP5 antagonist, SOST, and consequently are more refractory to inhibition by SOST. Further, Bhat used structure-based mutation analysis to show the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling. High bone mass (HBM) Note Bone mass density (BMD) and fracture rates vary among women of differing ethnicities. Most reports had suggested that BMD is highest in African Americans, lowest in Asians, and intermediate in Caucasians, yet Asians have lower fracture rates than Caucasians. Finkelstein et al. (2002) assessed lumbar spine and femoral neck BMD by dual-energy x-ray absorptiometry in 2277 (lumbar) and 2330 (femoral) premenopausal or early perimenopausal women (mean age, 46.2 yr) participating in the Study of Women's Health Across the Nation. When BMD was assessed in a subset of women weighing less than 70 kg and then adjusted for covariates, lumbar spine BMD was similar in African American, Chinese, and Japanese women and was lowest in Caucasian women. Femoral neck BMD was highest in African Americans and similar in Chinese, Japanese, and Caucasians. They also suggested that these findings may explain why Caucasian women have higher fracture rates than African Americans and Asians. Cytogenetics Little et al. also identified the same Gly171Val mutation in the LRP5 gene (G171V; 603506.0013) that results in an autosomal dominant high bone mass trait. Van Wesenbeeck et al. performed mutation analysis of the LRP5 gene in 10 families or isolated patients with various conditions of an increased bone density, including endosteal hyperostosis. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain, which is the same as for the G171V mutation that causes the high-bone-mass phenotype and most likely is disease-causing. Boyden et al. found that the expression of LRP5V171 did not activate signaling in the absence of Wnt-1. The activation of the signaling pathway in response to Wnt1 was the same with normal and mutant LRP5.They also tested the action of the endogenous antagonist of Wnt signaling, Dkk-1. Although Dkk-1 inhibited Wnt signaling in conjunction with wild-type LRP5, Dkk-1 inhibition of Wnt signaling was virtually abolished in cells expressing LRP5V171. These findings indicated that the mutation G171V, located in the first YWTD repeat of LRP5, results in increased Wnt signaling because of loss of Dkk antagonism to LRP5. However, Zhang et al. found that the third YWTD repeat (but not the first repeat domain) was required for DKK1-mediated antagonism. They found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperone protein for LRP5/6 that is required for transport of the co-receptors to cell surfaces, resulting in fewer LRP5 molecules on the cell surface. So they think that the G171V mutation may cause an increase in Wnt activity in osteoblasts by Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) Familial exudative vitreoretinopathy (FEVR) Note Familial exudative vitreoretinopathy (FEVR) is a welldefined inherited disorder of retinal vessel development (Benson, 1995). It is reported to have a penetrance of 100%, but clinical features can be highly variable even within the same family. Severely affected patients may be legally blind during the first decade of life, whereas mildly affected individuals may not even be aware of symptoms and may receive a diagnosis only by use of fluorescein angiography. Cytogenetics As reported by Toomes et al., mutations in LRP5 within the EVR1 locus can cause FEVR, accounting for 15% of the patients and indicating that other unidentified FEVR genes may be a more significant cause of the disease than previously thought. Jiao et al. studied three consanguineous families of European descent in which autosomal recessive FEVR was diagnosed in multiple individuals. Sequencing of LRP5 showed, in all three families, homozygosity for mutation in LRP5: R570Q, R752G, and E1367K. Thus, mutations in the LRP5 gene can cause autosomal recessive as well as autosomal dominant FEVR. Qin et al. screened 56 unrelated patients with FEVR (31 familial and 25 simplex cases) for possible mutations in LRP5 and Frizzled 4 (FZD4). Six novel mutations in either LRP5 or FZD4 were identified in six familial cases. Four novel mutations in LRP5 and one known mutation in FZD4 were detected in three simplex cases, and two of these patients carried 273 LRP5 (low density lipoprotein receptor-related protein 5) Zhong ZA, Williams BO syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146-51 compound heterozygous mutations in LRP5. They also demonstrated that reduced bone density is a common feature in patients with FEVR who harbor LRP5 mutations. 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 Obesity Note Obesity is a growing health care problem and a risk factor for common diseases such as diabetes, heart disease, and hypertension. LRP5 is highly expressed in many tissues, including hepatocytes and pancreatic beta cells. Some evidence has shown that LRP5 can bind apolipoprotein E (apoE), which raises the possibility that LRP5 plays a role in the hepatic clearance of apoE-containing chylomicron remnants, a major plasma lipoprotein carrying dietderived cholesterol. Using LRP5 knock-out mice model, Fujino et al. showed that LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca2+ in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-/- islets. The authors suggested that Wnt/LRP5 signaling contributes to the glucose-induced insulin secretion in the islets. Cytogenetics Guo et al. performed genotyping of 27 single nucleotide polymorphisms (SNPs), spaced 5 kb apart on average and covering the full transcript length of the LRP5 gene, using samples of 1873 Caucasian people from 405 nuclear families. They found that SNP4 (rs4988300) and SNP6 (rs634008), located in block 2 (intron 1), showed significant associations with obesity and BMI after Bonferroni correction (SNP4: p < 0.001 and p = 0.001, respectively; SNP6: p = 0.002 and 0.003, respectively). The common allele A for SNP4 and minor allele G for SNP6 were associated with an increased risk of obesity. Significant associations were also observed between the common haplotype A-G-GG of block 2 and obesity, BMI, fat mass, and PFM, with global empirical values of p < 0.001, p < 0.001, p = 0.003 and p = 0.074, respectively. They concluded that intronic variants of the LRP5 gene are markedly associated with obesity, possibly due to the role of LRP5 in the Wnt signaling pathway or lipid metabolism. Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines ME, Rosenquist T, Holdener BC. Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell. 2003 Feb 7;112(3):355-67 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 Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet. 2004 May;74(5):866-75 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 Hoang BH, Kubo T, Healey JH, Sowers R, Mazza B, Yang R, Huvos AG, Meyers PA, Gorlick R. Expression of LDL receptorrelated protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer. 2004 Mar;109(1):106-11 Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum Genet. 2004 Nov;75(5):878-84 Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, He X. A mechanism for Wnt coreceptor activation. Mol Cell. 2004 Jan 16;13(1):149-56 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 Zhang Y, Wang Y, Li X, Zhang J, Mao J, Li Z, Zheng J, Li L, Harris S, Wu D. The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol Cell Biol. 2004 Jun;24(11):4677-84 Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML. 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. Mol Cell Biol. 2005 Jun;25(12):4946-55 References Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995;93:473-521 Cheung WM, Jin LY, Smith DK, Cheung PT, Kwan EY, Low L, Kung AW. A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene. Bone. 2006 Sep;39(3):470-6 Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML. Osteoporosis-pseudoglioma Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW. Polymorphisms of the lowdensity lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet. 2006 Oct;43(10):798-803 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 274 LRP5 (low density lipoprotein receptor-related protein 5) Zhong ZA, Williams BO Lindvall C, Evans NC, Zylstra CR, Li Y, Alexander CM, Williams BO. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. J Biol Chem. 2006 Nov 17;281(46):35081-7 bone mass in both Chinese and whites. J Bone Miner Res. 2007 Mar;22(3):385-93 Guo Y, Rubin EM, Xie J, Zi X, Hoang BH. Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model. Clin Orthop Relat Res. 2008 Sep;466(9):2039-45 Semenov MV, He X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem. 2006 Dec 15;281(50):38276-84 Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008 Nov 28;135(5):825-37 Bhat BM, Allen KM, Liu W, Graham J, Morales A, Anisowicz A, Lam HS, McCauley C, Coleburn V, Cain M, Fortier E, Bhat RA, Bex FJ, Yaworsky PJ. Structure-based mutation analysis shows the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling. Gene. 2007 Apr 15;391(1-2):103-12 Badders NM, Goel S, Clark RJ, Klos KS, Kim S, Bafico A, Lindvall C, Williams BO, Alexander CM. The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS One. 2009 Aug 12;4(8):e6594 Björklund P, Akerström G, Westin G. An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling. PLoS Med. 2007 Nov 27;4(11):e328 Björklund P, Svedlund J, Olsson AK, Akerström G, Westin G. The internally truncated LRP5 receptor presents a therapeutic target in breast cancer. PLoS One. 2009;4(1):e4243 Drenser KA, Trese MT. Familial exudative vitreoretinopathy and osteoporosis-pseudoglioma syndrome caused by a mutation in the LRP5 gene. Arch Ophthalmol. 2007 Mar;125(3):431-2 Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res. 2009 Feb;24(2):171-8 Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, NelsonWilliams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007 Mar 2;315(5816):1278-82 This article should be referenced as such: Zhong ZA, Williams BO. LRP5 (low density lipoprotein receptor-related protein 5). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3):270-275. Xiong DH, Lei SF, Yang F, Wang L, Peng YM, Wang W, Recker RR, Deng HW. Low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms are associated with Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3) 275