11q13.2

BMND1,EVR1,EVR4,HBM,LR3,LRP-5,LRP-7,LRP7,OPPG,OPS,OPTA1,PCLD4,VBCH2

Hyperparathyroid tumors, breast cancer

According to Bjorklunds 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.

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

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 high-grade 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)

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.

Gong et al. found that OPPG carriers have reduced bone mass when compared with age- and gender-matched 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 gut-specific 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.

High bone mass (HBM)

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 Womens 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.

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 amino-terminal 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 Wnt-1 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 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 bone-specific 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.

Familial exudative vitreoretinopathy (FEVR)

Familial exudative vitreoretinopathy (FEVR) is a well-defined 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.

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 compound heterozygous mutations in LRP5. They also demonstrated that reduced bone density is a common feature in patients with FEVR who harbor LRP5 mutations.

Obesity

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 diet-derived 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.

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-G-G 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 lipi