Nomenclature: LGR4

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 951 11p14-p13 LGR4 leucine-rich repeat containing G protein-coupled receptor 4 16
Mouse 7 951 2 E3 Lgr4 leucine-rich repeat-containing G protein-coupled receptor 4 16
Rat 7 951 3q33 Lgr4 leucine-rich repeat-containing G protein-coupled receptor 4
Previous and Unofficial Names
GPR48
LGR4
leucine-rich repeat-containing G protein-coupled receptor 4
G-protein coupled receptor 48
G protein-coupled receptor 48
leucine-rich repeat-containing G-protein coupled receptor 4
A330106J01Rik
A930009A08Rik
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Complex of R-spondin 1 with LGR4 extracellular domain
PDB Id:  4KT1
Ligand:  R-spondin-1   This ligand is endogenous
Resolution:  2.5Å
Species:  Human
References:  28
Natural/Endogenous Ligand(s)
R-spondins
Comments: Proposed ligands, single publication
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
R-spondin-3 {Sp: Human} Hs Full agonist 8.66 pKd 6
pKd 8.66 (Kd 2.2x10-9 M) [6]
R-spondin-2 {Sp: Human} Hs Full agonist 12.52 pEC50 1
pEC50 12.52 (EC50 3x10-13 M) [1]
R-spondin-3 {Sp: Human} Hs Full agonist 10.7 pEC50 1
pEC50 10.7 (EC50 2x10-11 M) [1]
R-spondin-1 {Sp: Human} Hs Full agonist 10.7 pEC50 1
pEC50 10.7 (EC50 2x10-11 M) [1]
R-spondin-4 {Sp: Human} Hs Full agonist 10.05 pEC50 1
pEC50 10.05 (EC50 9x10-11 M) [1]
Agonist Comments
R-spondins bind to LGR4, which specifically associates with Frizzled and LRPs—proteins that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [1,3,25].
Primary Transduction Mechanisms
Transducer Effector/Response
Adenylate cyclase inhibition
Comments:  Although direct Gs protein coupling has not been demonstrated, LGR4 can increase intracellular cAMP levels, which activates cAMP-dependent PKA and directly regulates Pitx2 expression through CREB transcription factor binding to the Pitx2 promoter. LGR4 does not couple to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action [1].
References:  17,31
Tissue Distribution
Placenta, ovary, testis, adrenal, spinal cord, stomach, trachea, heart, pancreas, kidney, prostate, spleen
Species:  Human
Technique:  Northern Blot
References:  9
Pancreas, placenta, kidney, brain, heart
Species:  Human
Technique:  Northern Blot
References:  15
Cyclic endometrium
Species:  Human
Technique:  RT-PCR
References:  13
Kidney, adrenal gland, stomach, intestine, heart, bone/cartilage
Species:  Mouse
Technique:  Immunohistochemistry
References:  18
Testis, ovary, kidney, adrenal, bone, cartilage, eye, intestine, brain (hippocampus, ventricles, meninges, olfactory bulb, spinal cord), trachea (chondrocytes)
Species:  Mouse
Technique:  in situ hybridisation
References:  27
Ovarian granulosa cells, epithelial cells of oviduct and smooth muscle cells of the uterus
Species:  Mouse
Technique:  RT-PCR
References:  22
Tissue Distribution Comments
LGR4 is expressed at embryonic day 7 in the mouse indicating a potential role in development [15]. Zebrafish lgr4 is expressed in the neural plate border, Kupffer's vesicle, neural tube, otic vesicles, midbrain, eyes, forebrain, and brain ventricular zone, midbrain-hindbrain boundary, otic vesicles, pharyngeal arches, cranial cartilages, palatoquadrates, ceratohyals, cranial cavity, pectoral fin buds, brain ventricular zone, ciliary marginal zone, and digestive organs such as the intestine, liver, and pancreas (in situ hybridisation) [8].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Physiological Functions
Renal development
Species:  Mouse
Tissue:  Kidney
References:  11,22
Development of anterior segment of the mammalian eye
Species:  Mouse
Tissue:  Eye
References:  31
Embryonic growth, kidney and liver development
Species:  Mouse
Tissue:  Kidney, liver, embryo
References:  18
Epithelial-mesenchymal transition
Species:  Mouse
Tissue:  Epididymal duct, testis
References:  19
Physiological Functions Comments
LGR4 is required for Rspo3 signalling in vivo. It is cointernalised with Rspo3 by clathrin-mediated endocytosis [6]. LGR4 enhances aldosterone responsiveness in the kidney by activating mineralocorticoid receptor expression, suggesting that LGR4 may contribute to homeostasis of electrolytes and blood pressure and may be a candidate gene for pseudohypoaldosteronism type 1 (PHA1) [29].
Physiological Consequences of Altering Gene Expression
Embryonic lethality. Receptor knockout mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality
Species:  Mouse
Tissue:  Embryo
Technique:  Gene knockout
References:  18
Hypoplastic poorly convoluted tract, shortened efferent duct, and infertility. Receptor knockout mice show inhibited tube elongation of efferent ducts and epididymis. Immune cells infiltrate efferent ducts blocking transit of sperm and testicular fluid
Species:  Mouse
Tissue:  Male reproductive tract
Technique:  Gene knockouts
References:  14,19
Renal hypoplasia, elevated plasma creatine, reduced number and density of the glomerulus, premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockouts
References:  11,21
Overexpression of LGR4 increased both in vitro invasive activity and lung metastasis potency of HCT116 cells
Species:  Human
Tissue:  HCT116
Technique:  Gene over-expression
References:  4
Reduced keratinocyte and epithelial cell proliferation, regulated by HB-EGF mediated EGFR transactivation, and motility associated with mouse receptor knockout. the resulting phenotype is eyes open at birth
Species:  Mouse
Tissue:  Keratinocytes, epithelial cells
Technique:  Gene knockouts
References:  10,12,30
Receptor knockout causes anterior segment dysgenesis, including iris myogenesis, and early onset glaucoma, at early and late postnatal stages of eye development
Species:  Mouse
Tissue:  Eye
Technique:  Gene knockouts
References:  2
Lgr4-deficient mice showed partial impairment in hair follicle development with reduced expression of Edar, Lef1, and Shh in the epidermis. The observed phenotype is sparse head hair and focal alopecia behind their ears
Species:  Mouse
Tissue:  Hair follicle
Technique:  Gene knockouts
References:  20
Lgr4- hypomorphic mice lack a gall bladder and cystic duct without affecting the other tissues that derive from the same hepatic diverticulum
Species:  Mouse
Tissue:  Gall bladder
Technique:  Targeting in embryonic stem cells
References:  32
Delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also affected with downregulation of Atf4 target genes/proteins. Reduced kinetic indices of bone formation rate, bone mineral density and osteoid formation, with increast osteoclast activity
Species:  Mouse
Tissue:  Osteoblasts
Technique:  Gene knockouts
References:  17
Reduced metastatic potential. Depletion of endogenous LGR4 by RNA interference reduced the invasive potential of HeLa and Lewis lung carcinoma cells in vitro and in vivo
Species:  Human
Tissue:  HeLa and Lewis lung carcinoma cells
Technique:  RNA interference (RNAi)
References:  4-5
Physiological Consequences of Altering Gene Expression Comments
Lgr4 null mouse fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis, possibly because ATF4, a key transcription factor in erythropoiesis, is down-regulated [26]. Conditional knockout of Lgr4 leads to impaired ductal elongation and branchingmorphogenesis in mouse mammary glands [24]. Conditional knockout of Lgr4 in the oviduct impaired embryonic development due to impaired secretion of growth factors [21]. Conditional deletion of Lgr4 in theintestinal epithelium of adult mice impaired Wnt target gene expression and resulted in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition [1]. Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo [23].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005193 abnormal anterior eye segment morphology PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005204 abnormal canal of Schlemm morphology PMID: 18424556 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002660 abnormal caput epididymis morphology PMID: 17079737 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005099 abnormal ciliary body morphology PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0006000 abnormal corneal epithelium morphology PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005300 abnormal corneal stroma morphology PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001312 abnormal cornea morphology PMID: 18424556 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0004728 abnormal efferent ductules of testis PMID: 16406039 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0006319 abnormal epididymal fat pad morphology PMID: 16406039 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0004933 abnormal epididymis epithelium morphology PMID: 16406039 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002631 abnormal epididymis morphology PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0002631 abnormal epididymis morphology PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0004221 abnormal iridocorneal angle PMID: 18424556 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003453 abnormal keratinocyte physiology PMID: 17850793 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0002135 abnormal kidney morphology PMID: 15192078 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002135 abnormal kidney morphology PMID: 16785743 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001303 abnormal lens morphology PMID: 18424556 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003881 abnormal nephron morphology PMID: 16785743 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002160 abnormal reproductive system morphology PMID: 17079737 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0001919 abnormal reproductive system physiology PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0006416 abnormal rete testis morphology PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001325 abnormal retina morphology PMID: 18424556 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0006304 abnormal seminiferous epithelium morphology PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0006304 abnormal seminiferous epithelium morphology PMID: 16406039 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002673 abnormal sperm number PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0004884 abnormal testicular physiology PMID: 16406039 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0001146 abnormal testis morphology PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0001146 abnormal testis morphology PMID: 16406039 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002675 asthenozoospermia PMID: 17079737 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001304 cataracts PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0006233 corneal adhesion to iris PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005544 corneal deposits PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001314 corneal opacity PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005543 corneal thinning PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005542 corneal vascularization PMID: 18424556 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0001265 decreased body size PMID: 16406039 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0001262 decreased body weight PMID: 15192078 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001262 decreased body weight PMID: 18424556 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0001262 decreased body weight PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003092 decreased corneal stroma thickness PMID: 18424556 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0004929 decreased epididymis weight PMID: 17079737 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0009431 decreased fetal weight PMID: 16785743 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0003918 decreased kidney weight PMID: 15192078 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003918 decreased kidney weight PMID: 16785743 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0003402 decreased liver weight PMID: 15192078 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0004505 decreased renal glomerulus number PMID: 16785743 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008770 decreased survivor rate PMID: 18424556 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0006423 dilated rete testis PMID: 17079737 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008512 disorganized retinal inner nuclear layer PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008516 disorganized retinal outer nuclear layer PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002579 disorganized secondary lens fibers PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003984 embryonic growth retardation PMID: 18424556 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0001148 enlarged testes PMID: 15192078 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0004906 enlarged uterus PMID: 15192078 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0003595 epididymal cyst PMID: 16406039 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0004932 epididymis hypoplasia PMID: 16406039 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001302 eyelids open at birth PMID: 17850793 
Lgr4tm1.1Knis|Tg(KRT5-cre)1Tak Lgr4tm1.1Knis/Lgr4tm1.1Knis,Tg(KRT5-cre)1Tak/0
involves: 129P2/OlaHsd * C3H * C57BL/6 * SJL
MGI:1891468  MGI:1926776  MP:0001302 eyelids open at birth PMID: 17850793 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0004223 hypoplastic trabecular meshwork PMID: 18424556 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0005553 increased circulating creatinine level PMID: 16785743 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001313 increased incidence of corneal inflammation PMID: 18424556 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0004851 increased testis weight PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0001924 infertility PMID: 15192078 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0006226 iris hypoplasia PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0006230 iris stroma hypoplasia PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001321 large pupils PMID: 18424556 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0006208 lethality throughout fetal growth and development PMID: 16785743 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0001925 male infertility PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0001925 male infertility PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001297 microphthalmia PMID: 18424556 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002058 neonatal lethality PMID: 16785743 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0002081 perinatal lethality PMID: 15192078 
Lgr4+|Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4+
involves: 129P2/Ola * C57BL/6
MGI:1891468  MP:0002081 perinatal lethality PMID: 15192078 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002081 perinatal lethality PMID: 16785743 
Lgr4+|Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4+
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002081 perinatal lethality PMID: 16785743 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008528 polycystic kidney PMID: 16785743 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0001732 postnatal growth retardation PMID: 17079737 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001732 postnatal growth retardation PMID: 16785743 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
B6.Cg-Lgr4
MGI:1891468  MP:0002082 postnatal lethality PMID: 17079737 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0002082 postnatal lethality PMID: 17079737 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0002082 postnatal lethality PMID: 16406039 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0002083 premature death PMID: 16785743 
Lgr4Gt(pU-21)1Kymm Lgr4Gt(pU-21)1Kymm/Lgr4Gt(pU-21)1Kymm
CB.Cg-Lgr4
MGI:1891468  MP:0001923 reduced female fertility PMID: 17079737 
Lgr4tm1.2Knis Lgr4tm1.2Knis/Lgr4tm1.2Knis
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0003446 renal hypoplasia PMID: 16785743 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0006417 rete testis obstruction PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008067 retinal ganglion cell degeneration PMID: 18424556 
Lgr4Gt(pGT0TMpfs)1Wcs Lgr4Gt(pGT0TMpfs)1Wcs/Lgr4Gt(pGT0TMpfs)1Wcs
involves: 129P2/OlaHsd * C57BL/6 * CD-1
MGI:1891468  MP:0009248 small caput epididymis PMID: 16406039 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0001306 small lens PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008511 thin retinal inner nuclear layer PMID: 18424556 
Lgr4Gt(LST020)Byg Lgr4Gt(LST020)Byg/Lgr4Gt(LST020)Byg
involves: 129P2/OlaHsd * C57BL/6
MGI:1891468  MP:0008515 thin retinal outer nuclear layer PMID: 18424556 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Bone mineral density, low, susceptibility to
OMIM:  615311
References: 
Mutations not determined
Gene Expression and Pathophysiology Comments
Role in kidney development suggests that LGR4 may be involved in hereditary kidney disease [11]. LGR4 expression is upregulated in human colon carcinoma cells, correlated with lymph node metastasis and inversely associated with p27 expression [4]. LGR4 is significantly overexpressed in squamous cell carcinoma [7]. LGR4 is a permissive factor in the Wnt pathway in the intestine and, as such, a potential target for intestinal cancer therapy [23].
Biologically Significant Variants
Type:  Naturally occurring SNPs.
Species:  Human
Description:  V723G
SNP accession: 
Type:  Naturally occurring SNPs.
Species:  Human
Description:  I724F, low frequency (<10% in all tested populations)
SNP accession: 
Type:  Naturally occurring SNPs.
Species:  Human
Description:  D844G, low frequency (<10% in all tested populations)
SNP accession: 
Type:  Naturally occurring SNPs.
Species:  Human
Description:  S215G, low frequency (<10% in all tested populations)
SNP accession: 
Type:  Naturally occurring SNPs.
Species:  Human
Description:  P680S, low frequency (<10% in all tested populations)
SNP accession: 
Type:  Naturally occurring SNPs.
Species:  Human
Description:  R684G, low frequency (<10% in all tested populations)
SNP accession: 
Type:  SNP
Species:  Human
Change:  T709M
Global MAF (%):  3
Subpopulation MAF (%):  AFR|AMR|EUR: 3|6|3
Minor allele count:  A=0.026/57
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  1000 Genomes, Frequency
Type:  SNP
Species:  Human
Change:  A480V
Global MAF (%):  4
Subpopulation MAF (%):  AFR|AMR: 15|2
Minor allele count:  A=0.037/80
SNP accession: 
Validation:  1000 Genomes, HapMap, Frequency
Type:  SNP
Species:  Human
Change:  G363C
Global MAF (%):  1
Subpopulation MAF (%):  AMR|EUR: 1|1
Minor allele count:  A=0.007/15
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  1000 Genomes, Frequency
Available Assays
DiscoveRx PathHunter® CHO-K1 LGR4 β-Arrestin Orphan GPCR Cell Line (Cat no. 93-0516C2A)
PathHunter® eXpress LGR4 CHO-K1 β-Arrestin Orphan GPCR Assay (Cat no. 93-0516E2ACP1M)
more info

REFERENCES

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2. Damond F, Benard A, Ruelle J, Alabi A, Kupfer B, Gomes P, Rodes B, Albert J, Böni J, Garson J et al.. (2008) Quality control assessment of human immunodeficiency virus type 2 (HIV-2) viral load quantification assays: results from an international collaboration on HIV-2 infection in 2006. J. Clin. Microbiol.46 (6): 2088-91. [PMID:18434556]

3. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M et al.. (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature476 (7360): 293-7. [PMID:21727895]

4. Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, Uchida C, Hattori T, Oda T, Nakayama K et al.. (2006) Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res.66 (24): 11623-31. [PMID:17178856]

5. Gao Y, Shan ZY, Wang H, Zhang HM, Teng WP. (2009) Inhibitory effect of shRNA targeting GPR48 on invasion and metastasis of human cervical carcinoma cell line HeLa. Ai Zheng28 (2): 104-7. [PMID:19550120]

6. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C. (2011) LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep.12 (10): 1055-61. [PMID:21909076]

7. Gugger M, White R, Song S, Waser B, Cescato R, Rivière P, Reubi JC. (2008) GPR87 is an overexpressed G-protein coupled receptor in squamous cell carcinoma of the lung. Dis. Markers24 (1): 41-50. [PMID:18057535]

8. Hirose K, Shimoda N, Kikuchi Y. (2011) Expression patterns of lgr4 and lgr6 during zebrafish development. Gene Expr. Patterns11 (7): 378-83. [PMID:21570488]

9. Hsu SY, Liang SG, Hsueh AJ. (1998) Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol.12 (12): 1830-45. [PMID:9849958]

10. Jin C, Yin F, Lin M, Li H, Wang Z, Weng J, Liu M, Da Dong X, Qu J, Tu L. (2008) GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest. Ophthalmol. Vis. Sci.49 (10): 4245-53. [PMID:18487371]

11. Kato S, Matsubara M, Matsuo T, Mohri Y, Kazama I, Hatano R, Umezawa A, Nishimori K. (2006) Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice. Nephron Exp. Nephrol.104 (2): e63-75. [PMID:16785743]

12. Kato S, Mohri Y, Matsuo T, Ogawa E, Umezawa A, Okuyama R, Nishimori K. (2007) Eye-open at birth phenotype with reduced keratinocyte motility in LGR4 null mice. FEBS Lett.581 (24): 4685-90. [PMID:17850793]

13. Krusche CA, Kroll T, Beier HM, Classen-Linke I. (2007) Expression of leucine-rich repeat-containing G-protein-coupled receptors in the human cyclic endometrium. Fertil. Steril.87 (6): 1428-37. [PMID:17274992]

14. Lambot MA, Mendive F, Laurent P, Van Schoore G, Noël JC, Vanderhaeghen P, Vassart G. (2009) Three-dimensional reconstruction of efferent ducts in wild-type and Lgr4 knock-out mice. Anat Rec (Hoboken)292 (4): 595-603. [PMID:19301269]

15. Loh ED, Broussard SR, Kolakowski LF. (2001) Molecular characterization of a novel glycoprotein hormone G-protein-coupled receptor. Biochem. Biophys. Res. Commun.282 (3): 757-64. [PMID:11401528]

16. Loh ED, Broussard SR, Liu Q, Copeland NG, Gilbert DJ, Jenkins NA, Kolakowski LF. (2000) Chromosomal localization of GPR48, a novel glycoprotein hormone receptor like GPCR, in human and mouse with radiation hybrid and interspecific backcross mapping. Cytogenet. Cell Genet.89 (1-2): 2-5. [PMID:10894923]

17. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, Li XY, de Crombrugghe B, Höök M, Liu M. (2009) Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development136 (16): 2747-56. [PMID:19605502]

18. Mazerbourg S, Bouley DM, Sudo S, Klein CA, Zhang JV, Kawamura K, Goodrich LV, Rayburn H, Tessier-Lavigne M, Hsueh AJ. (2004) Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol. Endocrinol.18 (9): 2241-54. [PMID:15192078]

19. Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, Vassart G. (2006) Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev. Biol.290 (2): 421-34. [PMID:16406039]

20. Mohri Y, Kato S, Umezawa A, Okuyama R, Nishimori K. (2008) Impaired hair placode formation with reduced expression of hair follicle-related genes in mice lacking Lgr4. Dev. Dyn.237 (8): 2235-42. [PMID:18651655]

21. Mohri Y, Oyama K, Akamatsu A, Kato S, Nishimori K. (2011) Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. Dev. Dyn.240 (6): 1626-34. [PMID:21523854]

22. Mohri Y, Umezu T, Hidema S, Tomisawa H, Akamatsu A, Kato S, Nawa A, Nishimori K. (2010) Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Fertil. Steril.94 (7): 2878-81. [PMID:20638054]

23. Mustata RC, Van Loy T, Lefort A, Libert F, Strollo S, Vassart G, Garcia MI. (2011) Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep.12 (6): 558-64. [PMID:21508962]

24. Oyama K, Mohri Y, Sone M, Nawa A, Nishimori K. (2011) Conditional knockout of Lgr4 leads to impaired ductal elongation and branching morphogenesis in mouse mammary glands. Sex Dev5 (4): 205-12. [PMID:21791950]

25. Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A, Zietzling S, Beck V, Therier M, Isken A et al.. (2012) R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE7 (7): e40976. [PMID:22815884]

26. Song H, Luo J, Luo W, Weng J, Wang Z, Li B, Li D, Liu M. (2008) Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J. Biol. Chem.283 (52): 36687-97. [PMID:18955481]

27. Van Schoore G, Mendive F, Pochet R, Vassart G. (2005) Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem. Cell Biol.124 (1): 35-50. [PMID:16028069]

28. Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X. (2013) Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev.27 (12): 1339-44. [PMID:23756652]

29. Wang J, Li X, Ke Y, Lu Y, Wang F, Fan N, Sun H, Zhang H, Liu R, Yang J et al.. (2012) GPR48 increases mineralocorticoid receptor gene expression. J. Am. Soc. Nephrol.23 (2): 281-93. [PMID:22135314]

30. Wang Z, Jin C, Li H, Li C, Hou Q, Liu M, Dong Xda E, Tu L. (2010) GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation. FEBS Lett.584 (18): 4057-62. [PMID:20732323]

31. Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, Tu L, Ai D, Li D, Wang J, Martin JF, Amendt BA, Liu M. (2008) Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc. Natl. Acad. Sci. U.S.A.105 (16): 6081-6. [PMID:18424556]

32. Yamashita R, Takegawa Y, Sakumoto M, Nakahara M, Kawazu H, Hoshii T, Araki K, Yokouchi Y, Yamamura K. (2009) Defective development of the gall bladder and cystic duct in Lgr4- hypomorphic mice. Dev. Dyn.238 (4): 993-1000. [PMID:19301403]

To cite this database page, please use the following:

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: LGR4. Last modified on 25/03/2014. Accessed on 18/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=147.

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