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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.
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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).
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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.
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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
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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
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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