LRP5
protein-codingLDL receptor related protein 5, the group of Low density lipoprotein receptors
Gene summary
This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
- LRP7
- OPPG
- EVR1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~136.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009820
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0700228
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009820
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0700228
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011877
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011877
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019516
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009820
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008265
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011151
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0011151
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0015800
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700228
Submitter: ClinGen
The *LRP5* gene was first reported in relation to osteoporosis-pseudoglioma syndrome in 1996 (Gong et al., PMID: 11719191) and in relation to autosomal recessive cases of familial exudative vitreoretinopathy in 2004 (Jiao et al., PMID: 15346351). Affected individuals with causal biallelic variants in *LRP5* have since been identified in a number of other publications, with osteoporosis-pseudoglioma syndrome (MIM#: 259770) describing the subset of cases exhibiting congenital or early childhood onset of blindness caused by ocular defects such as retinal folds, severe retinal detachment, optic disc traction, and abnormal vascular growth including hyaloid vascular remnants in the vitreous body, as well as juvenile onset of osteoporosis, reduced bone mineral density, and recurrent fractures. Additional features of these cases can include microphthalmos, moderate intellectual disability, short stature, joint laxity, and/or hypotonia. The subset of cases diagnosed with familial exudative vitreoretinopathy (MIM#: 601813) generally exhibit early onset of visual problems ranging from peripheral visual disturbances to blindness in some cases, with underlying peripheral retinal avascularity, retinal neovascularization, retinal folds, retinal exudate, vitreoretinal traction, and retinal detachment, as well as reduced bone mineral density and predisposition to fractures. Some of the disease-causing *LRP5* variants overlap between cases with different diagnoses. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (biallelic loss of function in the *LRP5* gene product) and mode of inheritance (autosomal recessive) to be consistent among unrelated patients diagnosed with either osteoporosis-pseudoglioma syndrome (MIM#: 259770) or familial exudative vitreoretinopathy 4 (MIM#: 601813). The phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped into a single disease entity, referred to as LRP5-related exudative vitreoretinopathy. Additional disease entities, including autosomal dominant familial exudative vitreoretinopathy, have been asserted in relation to monoallelic variants in *LRP5*. While this phenotype is characterized by some similar clinical characteristics and overlapping variants, its different mode of inheritance and incomplete penetrance have raised the possibility of a different or incompletely characterized mechanism of pathogenesis, including additional unidentified variants in other loci or within *LRP5* itself. Thus, *LRP5* has been separately curated for its relationship to these other disease entities. Seventeen suspected disease-causing variants were scored as part of this curation (six missense, three frameshift, six nonsense, one C-terminal deletion, and one affecting splicing), which have been collectively reported in thirteen probands in six publications (PMID: 15346351, PMID: 11719191, PMID: 20034086, PMID: 18602879, PMID: 15981244, PMID: 27228167). Nine probands were homozygous for the variant of interest, eight of whom were reported to have consanguineous parents (PMID: 15346351, PMID: 11719191, PMID: 18602879). The other four probands were compound heterozygotes within the *LRP5* locus (PMID: 20034086, PMID: 15981244). The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by nonsense or frameshift variants predicted to trigger absence of the gene product (PMID: 18602879, PMID: 11719191, PMID: 15981244). All probands harboring two predicted null variants have been diagnosed with osteoporosis-pseudoglioma syndrome rather than familial exudative vitreoretinopathy (PMID: 18602879, PMID: 11719191). Three studies showing linkage of the clinical phenotypes to the *LRP5* locus were available in these publications (PMID: 8659519, PMID: 15346351, PMID: 18602879), and contributed to the scoring of the gene-disease relationship. More case-level data was available, but was not scored as part of this curation as the maximum scoring for this evidence type had already been reached. This gene-disease association is also supported by experimental evidence that *LRP5* encodes a co-receptor for canonical Wnt signaling (PMID: 11336703), consistent with the known role of this signaling pathway in mediating bone formation (PMID: 23514963). This biochemical function matches that of the FZD4 receptor, which is encoded by a gene in which monoallelic variants cause familial exudative vitreoretinopathy 1, with an autosomal dominant pattern of inheritance (PMID: 12172548). While *LRP5* is ubiquitously expressed throughout human tissues, its first expression in embryonic bone coincides with cell differentiation into osteoblasts and the beginning of membranous ossification (PMID: 11719191). A dominant negative C-terminally truncated fragment of LRP5 has been shown to inhibit the bone accrual / thickening of cultured bone explants (PMID: 11719191). Finally, a mouse with biallelic loss-of-function mutations in *Lrp5* recapitulates human patient phenotypes including early onset of decreased osteoblast proliferation, reduced bone mineral density, remnants of the hyaloid vascular system, and failure of macrophage-mediated endothelial cell apoptosis (PMID: 11956231). In summary, *LRP5* is definitively associated with LRP5-related exudative vitreoretinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on March 2nd, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0009395
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007764
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0044327
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0011151
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009820
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011877
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0044327
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0044327
Submitter: ClinGen
*LRP5* was first reported in relation to autosomal dominant polycystic liver disease (ADPLD) with or without kidney cysts in 2014 (Cnoseen et al., PMID: 24706814). Of note, *LRP5* is associated with a number of gene-disease relationships in OMIM. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, given differences in phenotype and inheritance patterns, these different clinical entities were split. This curation focuses only on the association between *LRP5* and ADPLD with or without kidney cysts. Four variants (all missense) that have been reported in *LRP5* probands in one publication (PMID: 24706814) are included in this curation. Given this curation focuses on monoallelic disease, publications supporting the role of *LRP5* in modifying the phenotype in patients with an alternate genetic mechanism for their cystic disease were not included in this curation. This gene-disease association is also supported by expression studies that demonstrated *LRP5* expression in liver tissue (PMID: 24706814) and studies that demonstrate that *LRP5* has a role in the WNT-signaling pathway that may be associated with polycystic liver disease (PMID: 30361437). In summary, there is limited evidence to support a gene-disease relationship between *LRP5* and ADPLD with or without kidney cysts. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was originally approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on August 12th, 2020 (SOP Version 7). This gene-disease relationship was re-evaluated on November 13th, 2023 (SOP Version 9). As a result of this re-evaluation, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0044271
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0001071
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0044327
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007764
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011151
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009820
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007764
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal; Musculoskeletal; Ophthalmologic; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Digenic inheritance (with FZD4) has been reported in Exudative vitreoretinopathy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LRP5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002335.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 19 | 604 | 4 | 627 | ||
| missense | 16 | 96 | 1136 | 50 | 3 | 1301 |
| nonsense | 27 | 16 | 1 | 44 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 48 | 29 | 2 | 79 | ||
| splice donor/acceptor (+/-2bp) | 10 | 24 | 8 | 42 | ||
| Total | 102 | 166 | 1166 | 654 | 7 | 2095 |
Highest pathogenic variant AF is 0.00016538045
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002326.2 | 23 | MANE Select | |
| Ensembl | ENSP00000294304.6 | 23 | MANE Select | |
| RefSeq | NP_001278831.1 | 16 | Standard | |
| Ensembl | ENSP00000435315.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lrp5 | Danio rerio | Structure: neuromast hair cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gastric cancer - Homo sapiens (human)
- mTOR signaling pathway - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Hepatocellular carcinoma - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
Biological Process
- gastrulation with mouth forming second
- positive regulation of mesenchymal cell proliferation
- osteoblast development
- glucose catabolic process
- endocytosis
Molecular Function
- protein binding
- Wnt-protein binding
- toxin transmembrane transporter activity
- Wnt-activated receptor activity
- coreceptor activity involved in Wnt signaling pathway
Cellular Component
- endoplasmic reticulum
- plasma membrane
- integral component of membrane
- receptor complex
- Wnt-Frizzled-LRP5/6 complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000294304
- Coding exons
- 23
- Length
- 136667
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 39
- Defined
- 125748
- p
- 0.000155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.67 | 946 | 1.10e+3 | 0.859 | 0.0000833 | 10542 |
| Missense (PolyPhen) | 289 | 405.56 | 0.71259 | 3778 | ||
| Synonymous | -1.15 | 541 | 508 | 1.06 | 0.0000442 | 3275 |
| Loss of Function | 5.94 | 15 | 67.8 | 0.221 | 0.00000346 | 713 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00017 | 0.00017 | rare |
| South Asian | 0.000099 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins (PubMed:11336703, PubMed:11448771, PubMed:15778503, PubMed:11719191, PubMed:15908424, PubMed:16252235). Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration (PubMed:11336703, PubMed:11719191). In particular, may play an important role in the development of the posterior patterning of the epiblast during gastrulation (By similarity). During bone development, regulates osteoblast proliferation and differentiation thus determining bone mass (PubMed:11719191). Mechanistically, the formation of the signaling complex between Wnt ligand, frizzled receptor and LRP5 coreceptor promotes the recruitment of AXIN1 to LRP5, stabilizing beta- catenin/CTNNB1 and activating TCF/LEF-mediated transcriptional programs (PubMed:11336703, PubMed:25920554, PubMed:24706814, PubMed:14731402). Acts as a coreceptor for non-Wnt proteins, such as norrin/NDP. Binding of norrin/NDP to frizzled 4/FZD4-LRP5 receptor complex triggers beta-catenin/CTNNB1-dependent signaling known to be required for retinal vascular development (PubMed:27228167, PubMed:16252235). Plays a role in controlling postnatal vascular regression in retina via macrophage-induced endothelial cell apoptosis (By similarity). {ECO:0000250|UniProtKB:Q91VN0, ECO:0000269|PubMed:11336703, ECO:0000269|PubMed:11448771, ECO:0000269|PubMed:11719191, ECO:0000269|PubMed:14731402, ECO:0000269|PubMed:15778503, ECO:0000269|PubMed:15908424, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:24706814, ECO:0000269|PubMed:25920554, ECO:0000269|PubMed:27228167}.;
- Disease
- DISEASE: Vitreoretinopathy, exudative 1 (EVR1) [MIM:133780]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history. {ECO:0000269|PubMed:27228167}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vitreoretinopathy, exudative 4 (EVR4) [MIM:601813]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. {ECO:0000269|PubMed:15024691, ECO:0000269|PubMed:15346351, ECO:0000269|PubMed:15981244, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:16929062, ECO:0000269|PubMed:19324841, ECO:0000269|PubMed:20340138, ECO:0000269|PubMed:24715757}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. {ECO:0000269|PubMed:14727154, ECO:0000269|PubMed:15824851, ECO:0000269|PubMed:16234968}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Osteoporosis-pseudoglioma syndrome (OPPG) [MIM:259770]: A disease characterized by congenital or infancy-onset blindness and severe juvenile-onset osteoporosis and spontaneous fractures. Additional clinical manifestations may include microphthalmos, abnormalities of the iris, lens or vitreous, cataracts, short stature, microcephaly, ligamental laxity, mental retardation and hypotonia. {ECO:0000269|PubMed:11719191, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:16679074, ECO:0000269|PubMed:17437160, ECO:0000269|PubMed:18602879}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: High bone mass trait (HBM) [MIM:601884]: Rare phenotype characterized by exceptionally dense bones. HBM individuals show otherwise a completely normal skeletal structure and no other unusual clinical findings. {ECO:0000269|PubMed:11741193, ECO:0000269|PubMed:12015390, ECO:0000269|PubMed:15143163, ECO:0000269|PubMed:15824861, ECO:0000269|PubMed:17295608}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Endosteal hyperostosis, Worth type (WENHY) [MIM:144750]: An autosomal dominant sclerosing bone dysplasia clinically characterized by elongation of the mandible, increased gonial angle, flattened forehead, and the presence of a slowly enlarging osseous prominence of the hard palate (torus palatinus). Serum calcium, phosphorus and alkaline phosphatase levels are normal. Radiologically, it is characterized by early thickening of the endosteum of long bones, the skull and of the mandible. With advancing age, the trabeculae of the metaphysis become thickened. WENHY becomes clinically and radiologically evident by adolescence, does not cause deformity except in the skull and mandible, and is not associated with bone pain or fracture. Affected patients have normal height, proportion, intelligence and longevity. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteopetrosis, autosomal dominant 1 (OPTA1) [MIM:607634]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. OPTA1 is an autosomal dominant form characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Van Buchem disease 2 (VBCH2) [MIM:607636]: VBCH2 is an autosomal dominant sclerosing bone dysplasia characterized by cranial osteosclerosis, thickened calvaria and cortices of long bones, enlarged mandible and normal serum alkaline phosphatase levels. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polycystic liver disease 4 with or without kidney cysts (PCLD4) [MIM:617875]: A form of polycystic liver disease, an autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. PCLD4 patients may also develop kidney cysts that usually do not result in clinically significant renal disease. {ECO:0000269|PubMed:24706814, ECO:0000269|PubMed:28375157}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=LRP5 variations may act as a disease modifier in autosomal dominant polycystic kidney disease (ADPKD) in patients who have causative mutations in PKD1. May contribute to the disease phenotype heterogeneity and hepatic cystogenesis. {ECO:0000269|PubMed:25920554}.;
Recessive Scores
- pRec
- 0.104
Intolerance Scores
- LoFtool
- 0.0154
- RVIS EVS
- -3.72
- RVIS percentile EVS
- 0.24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.976
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |