Atlas of Genetics and Cytogenetics in Oncology and Haematology


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LRP5 (low density lipoprotein receptor-related protein 5)

Identity

Other namesBMND1
EVR1
EVR4
HBM
LR3
LRP7
OPPG
OPS
OPTA1
VBCH2
HGNC (Hugo) LRP5
LocusID (NCBI) 4041
Location 11q13.2
Location_base_pair Starts at 68080077 and ends at 68216743 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Exon count: 23; coding exon count: 23.
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.

Protein

 
  Schematic diagram of human LRP5, 1615 aa. (from He et al., Development. 2004 Apr;131(8):1663-77).
Description LRP5 contains a large extracellular domain (ECD) making up over 85% of the approximately 1600-amino-acid 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.
Expression Widely expressed, with the highest level of expression in the liver.
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).
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.

Mutations

 
  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):1663-77).
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.
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/beta-catenin signaling pathway in hyperparathyroid tumors and mammary gland tumorigenesis.

Implicated in

Entity 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 (LRP5Δ666-809) 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.
  
Entity 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 high-grade osteosarcoma (Hoang et al., 2004). Dominant negative LRP5 showed inhibition of osteosarcoma tumorigenicity and metastasis in mouse model (Guo et al., 2008).
  
Entity 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.
Cytogenetics 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.
  
Entity 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 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.
  
Entity Familial exudative vitreoretinopathy (FEVR)
Note 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.
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 compound heterozygous mutations in LRP5. They also demonstrated that reduced bone density is a common feature in patients with FEVR who harbor LRP5 mutations.
  
Entity 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 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.
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-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
  

External links

Nomenclature
HGNC (Hugo)LRP5   6697
Cards
AtlasLRP5ID44282ch11q13
Entrez_Gene (NCBI)LRP5  4041  low density lipoprotein receptor-related protein 5
GeneCards (Weizmann)LRP5
Ensembl (Hinxton)ENSG00000162337 [Gene_View]  chr11:68080077-68216743 [Contig_View]  LRP5 [Vega]
ICGC DataPortalENSG00000162337
cBioPortalLRP5
AceView (NCBI)LRP5
Genatlas (Paris)LRP5
WikiGenes4041
SOURCE (Princeton)NM_001291902 NM_002335
Genomic and cartography
GoldenPath (UCSC)LRP5  -  11q13.2   chr11:68080077-68216743 +  11q13.4   [Description]    (hg19-Feb_2009)
EnsemblLRP5 - 11q13.4 [CytoView]
Mapping of homologs : NCBILRP5 [Mapview]
OMIM133780   144750   166710   259770   601813   601884   603506   607634   607636   
Gene and transcription
Genbank (Entrez)AA279383 AA953315 AB017498 AF064548 AF077820
RefSeq transcript (Entrez)NM_001291902 NM_002335
RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NG_015835 NT_167190 NW_001838025 NW_004929380
Consensus coding sequences : CCDS (NCBI)LRP5
Cluster EST : UnigeneHs.6347 [ NCBI ]
CGAP (NCI)Hs.6347
Alternative Splicing : Fast-db (Paris)GSHG0005050
Alternative Splicing GalleryENSG00000162337
Gene ExpressionLRP5 [ NCBI-GEO ]     LRP5 [ SEEK ]   LRP5 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO75197 (Uniprot)
NextProtO75197  [Medical]
With graphics : InterProO75197
Splice isoforms : SwissVarO75197 (Swissvar)
Domaine pattern : Prosite (Expaxy)LDLRA_1 (PS01209)    LDLRA_2 (PS50068)    LDLRB (PS51120)   
Domains : Interpro (EBI)6-blade_b-propeller_TolB-like [organisation]   EG-like_dom [organisation]   LDLR_class-A_CS [organisation]   LDLR_classB_rpt [organisation]   LDrepeatLR_classA_rpt [organisation]   Low_density_Lipo_rcpt-rel_p5/6 [organisation]  
Related proteins : CluSTrO75197
Domain families : Pfam (Sanger)Ldl_recept_a (PF00057)    Ldl_recept_b (PF00058)   
Domain families : Pfam (NCBI)pfam00057    pfam00058   
Domain families : Smart (EMBL)EGF (SM00181)  LDLa (SM00192)  LY (SM00135)  
DMDM Disease mutations4041
Blocks (Seattle)O75197
Human Protein AtlasENSG00000162337 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO75197
HPRD04616
IPIIPI00744811   IPI00980932   IPI00981545   
Protein Interaction databases
DIP (DOE-UCLA)O75197
IntAct (EBI)O75197
FunCoupENSG00000162337
BioGRIDLRP5
InParanoidO75197
Interologous Interaction database O75197
IntegromeDBLRP5
STRING (EMBL)LRP5
Ontologies - Pathways
Ontology : AmiGOgastrulation with mouth forming second  positive regulation of mesenchymal cell proliferation  osteoblast development  protein binding  mitochondrion  endoplasmic reticulum  plasma membrane  glucose catabolic process  endocytosis  cholesterol metabolic process  regulation of blood pressure  positive regulation of cell proliferation  anterior/posterior pattern specification  coreceptor activity  integral component of membrane  Wnt signaling pathway  Wnt-protein binding  toxin transporter activity  embryonic limb morphogenesis  positive regulation of osteoblast proliferation  somatic stem cell maintenance  extracellular matrix-cell signaling  cell migration involved in gastrulation  cholesterol homeostasis  embryonic digit morphogenesis  Wnt-activated receptor activity  regulation of apoptotic process  receptor complex  response to peptide hormone  Wnt signaling pathway involved in dorsal/ventral axis specification  positive regulation of fat cell differentiation  negative regulation of osteoblast differentiation  positive regulation of mitosis  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  bone remodeling  regulation of bone remodeling  bone marrow development  embryonic camera-type eye morphogenesis  positive regulation of sequence-specific DNA binding transcription factor activity  anatomical structure regression  retina morphogenesis in camera-type eye  embryonic retina morphogenesis in camera-type eye  canonical Wnt signaling pathway  canonical Wnt signaling pathway  bone morphogenesis  branching involved in mammary gland duct morphogenesis  adipose tissue development  cell-cell signaling involved in mammary gland development  regulation of canonical Wnt signaling pathway  regulation of insulin secretion involved in cellular response to glucose stimulus  retinal blood vessel morphogenesis  negative regulation of protein serine/threonine kinase activity  apoptotic process involved in patterning of blood vessels  
Ontology : EGO-EBIgastrulation with mouth forming second  positive regulation of mesenchymal cell proliferation  osteoblast development  protein binding  mitochondrion  endoplasmic reticulum  plasma membrane  glucose catabolic process  endocytosis  cholesterol metabolic process  regulation of blood pressure  positive regulation of cell proliferation  anterior/posterior pattern specification  coreceptor activity  integral component of membrane  Wnt signaling pathway  Wnt-protein binding  toxin transporter activity  embryonic limb morphogenesis  positive regulation of osteoblast proliferation  somatic stem cell maintenance  extracellular matrix-cell signaling  cell migration involved in gastrulation  cholesterol homeostasis  embryonic digit morphogenesis  Wnt-activated receptor activity  regulation of apoptotic process  receptor complex  response to peptide hormone  Wnt signaling pathway involved in dorsal/ventral axis specification  positive regulation of fat cell differentiation  negative regulation of osteoblast differentiation  positive regulation of mitosis  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  bone remodeling  regulation of bone remodeling  bone marrow development  embryonic camera-type eye morphogenesis  positive regulation of sequence-specific DNA binding transcription factor activity  anatomical structure regression  retina morphogenesis in camera-type eye  embryonic retina morphogenesis in camera-type eye  canonical Wnt signaling pathway  canonical Wnt signaling pathway  bone morphogenesis  branching involved in mammary gland duct morphogenesis  adipose tissue development  cell-cell signaling involved in mammary gland development  regulation of canonical Wnt signaling pathway  regulation of insulin secretion involved in cellular response to glucose stimulus  retinal blood vessel morphogenesis  negative regulation of protein serine/threonine kinase activity  apoptotic process involved in patterning of blood vessels  
Pathways : KEGGWnt signaling pathway   
Protein Interaction DatabaseLRP5
Wikipedia pathwaysLRP5
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)LRP5
snp3D : Map Gene to Disease4041
SNP (GeneSNP Utah)LRP5
SNP : HGBaseLRP5
Genetic variants : HAPMAPLRP5
Exome VariantLRP5
1000_GenomesLRP5 
ICGC programENSG00000162337 
Somatic Mutations in Cancer : COSMICLRP5 
CONAN: Copy Number AnalysisLRP5 
Mutations and Diseases : HGMDLRP5
Genomic VariantsLRP5  LRP5 [DGVbeta]
dbVarLRP5
ClinVarLRP5
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM133780    144750    166710    259770    601813    601884    603506    607634    607636   
MedgenLRP5
GENETestsLRP5
Disease Genetic AssociationLRP5
Huge Navigator LRP5 [HugePedia]  LRP5 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneLRP5
Homology/Alignments : Family Browser (UCSC)LRP5
Phylogenetic Trees/Animal Genes : TreeFamLRP5
Chemical/Protein Interactions : CTD4041
Chemical/Pharm GKB GenePA30455
Clinical trialLRP5
Cancer Resource (Charite)ENSG00000162337
Other databases
Other databaseThe Wnt Homepage
Other databaseLRP/Arrow
Probes
Litterature
PubMed185 Pubmed reference(s) in Entrez
CoreMineLRP5
iHOPLRP5
OncoSearchLRP5

Bibliography

Familial exudative vitreoretinopathy.
Benson WE.
Trans Am Ophthalmol Soc. 1995;93:473-521.
PMID 8719692
 
Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.
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.
Am J Hum Genet. 1996 Jul;59(1):146-51.
PMID 8659519
 
High bone density due to a mutation in LDL-receptor-related protein 5.
Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP.
N Engl J Med. 2002 May 16;346(20):1513-21.
PMID 12015390
 
Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity.
Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines ME, Rosenquist T, Holdener BC.
Cell. 2003 Feb 7;112(3):355-67.
PMID 12581525
 
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 RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W.
Am J Hum Genet. 2003 Mar;72(3):763-71. Epub 2003 Feb 10.
PMID 12579474
 
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.
Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE.
Am J Hum Genet. 2004 May;74(5):866-75. Epub 2004 Apr 7.
PMID 15077203
 
LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.
He X, Semenov M, Tamai K, Zeng X.
Development. 2004 Apr;131(8):1663-77. (REVIEW)
PMID 15084453
 
Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma.
Hoang BH, Kubo T, Healey JH, Sowers R, Mazza B, Yang R, Huvos AG, Meyers PA, Gorlick R.
Int J Cancer. 2004 Mar;109(1):106-11.
PMID 14735475
 
Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5.
Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF.
Am J Hum Genet. 2004 Nov;75(5):878-84. Epub 2004 Sep 2.
PMID 15346351
 
A mechanism for Wnt coreceptor activation.
Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, He X.
Mol Cell. 2004 Jan 16;13(1):149-56.
PMID 14731402
 
Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.
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.
Am J Hum Genet. 2004 Apr;74(4):721-30. Epub 2004 Mar 11.
PMID 15024691
 
The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd.
Zhang Y, Wang Y, Li X, Zhang J, Mao J, Li Z, Zheng J, Li L, Harris S, Wu D.
Mol Cell Biol. 2004 Jun;24(11):4677-84.
PMID 15143163
 
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 SL, Van Hul W, Williams BO, Warman ML.
Mol Cell Biol. 2005 Jun;25(12):4946-55.
PMID 15923613
 
A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene.
Cheung WM, Jin LY, Smith DK, Cheung PT, Kwan EY, Low L, Kung AW.
Bone. 2006 Sep;39(3):470-6. Epub 2006 May 6.
PMID 16679074
 
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 YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW.
J Med Genet. 2006 Oct;43(10):798-803. Epub 2006 May 24.
PMID 16723389
 
The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis.
Lindvall C, Evans NC, Zylstra CR, Li Y, Alexander CM, Williams BO.
J Biol Chem. 2006 Nov 17;281(46):35081-7. Epub 2006 Sep 13.
PMID 16973609
 
LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST.
Semenov MV, He X.
J Biol Chem. 2006 Dec 15;281(50):38276-84. Epub 2006 Oct 19.
PMID 17052975
 
Structure-based mutation analysis shows the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling.
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.
Gene. 2007 Apr 15;391(1-2):103-12. Epub 2006 Dec 29.
PMID 17276019
 
An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling.
Bjorklund P, Akerstrom G, Westin G.
PLoS Med. 2007 Nov 27;4(11):e328.
PMID 18044981
 
Familial exudative vitreoretinopathy and osteoporosis-pseudoglioma syndrome caused by a mutation in the LRP5 gene.
Drenser KA, Trese MT.
Arch Ophthalmol. 2007 Mar;125(3):431-2.
PMID 17353424
 
LRP6 mutation in a family with early coronary disease and metabolic risk factors.
Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP.
Science. 2007 Mar 2;315(5816):1278-82.
PMID 17332414
 
Low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms are associated with bone mass in both Chinese and whites.
Xiong DH, Lei SF, Yang F, Wang L, Peng YM, Wang W, Recker RR, Deng HW.
J Bone Miner Res. 2007 Mar;22(3):385-93.
PMID 17241106
 
Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model.
Guo Y, Rubin EM, Xie J, Zi X, Hoang BH.
Clin Orthop Relat Res. 2008 Sep;466(9):2039-45. Epub 2008 Jun 20.
PMID 18566875
 
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schutz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G.
Cell. 2008 Nov 28;135(5):825-37.
PMID 19041748
 
The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage.
Badders NM, Goel S, Clark RJ, Klos KS, Kim S, Bafico A, Lindvall C, Williams BO, Alexander CM.
PLoS One. 2009 Aug 12;4(8):e6594.
PMID 19672307
 
The internally truncated LRP5 receptor presents a therapeutic target in breast cancer.
Bjorklund P, Svedlund J, Olsson AK, Akerstrm G, Westin G.
PLoS One. 2009;4(1):e4243. Epub 2009 Jan 22.
PMID 19158955
 
Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone.
Williams BO, Insogna KL.
J Bone Miner Res. 2009 Feb;24(2):171-8. (REVIEW)
PMID 19072724
 
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Contributor(s)

Written06-2010Zhendong Alex Zhong, Bart O Williams
Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan 49503-2518, USA

Citation

This paper 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):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/LRP5ID44282ch11q13.html

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