LRP4
protein-codingLDL receptor related protein 4, the group of Low density lipoprotein receptors
Gene summary
This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~61.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0017838
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: ClinGen
The LRP4 gene is located on chromosome 11 at 11p11.2, encodes a receptor for agrin and is critical for the formation and maintenance of the neuromuscular junction. LRP4 was first reported in relation to autosomal recessive Cenani-Lenz syndactyly syndrome in 2010 (Li et al., PMID: 20381006). Cenani-Lenz syndactyly syndrome is characterized by syndactyly and/or oligodactyly and commonly presents with kidney anomalies. Some patients present with sclerosteosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, congenital myasthenic syndrome 17 (OMIM:616304) has been split into a separate disease entity, Cenani-Lenz syndactyly syndrome (OMIM:212780) and sclerosteosis 2 (OMIM:614305) have been lumped together. The split curation for autosomal recessive congenital myasthenic syndrome 17 has been curated separately. Sixteen variants (missense, canonical splice site, and frameshift) that have been reported in 14 probands in seven publications (PMIDs: 20381006, 21471202, 28559208, 29524275, 32286743, 33179409, 35052419) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function, causing increased WNT signaling. This gene-disease relationship is also supported by animal models, expression studies, biochemical function, and in vitro functional assays (PMIDs: 21471202, 28477420, 30327840, 34857885). The homozygous knockin mouse model displayed increased bone mass (PMID: 28477420) and the homozygous knockdown of Zebrafish lrp4 resulted in syndactyly (PMID: 30327840). Multiple variants showed impaired ability to inhibit WNT signaling (PMIDs: 30327840, 34857885). LRP4 is expressed in osteoblasts and osteocytes, is a facilitator of SOST inhibition of Wnt1/β-catenin signaling, and binds with SOST which is associated with recessive forms of sclerosteosis per ClinGen’s Dosage Sensitivity Working Group. In summary, there is definitive evidence supporting the relationship between LRP4 and autosomal recessive Cenani-Lenz syndactyly syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 04.21.2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014578
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014578
Submitter: ClinGen
The LRP4 gene is located on chromosome 11 at 11p11.2, encodes a receptor for agrin and is critical for the formation and maintenance of the neuromuscular junction. LRP4 was first reported in relation to autosomal recessive congenital myasthenic syndrome 17 in 2014 (Ohkawara et al., PMID: 24234652). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, congenital myasthenic syndrome 17 (OMIM:616304) has been split into a separate disease entity, Cenani-Lenz syndactyly syndrome (OMIM:212780) and sclerosteosis 2 (OMIM:614305) have been lumped together. The split curation for autosomal recessive Cenani-Lenz syndactyly syndrome has been curated separately. Two variants (c.3697G>A (p.Glu1233Lys) and c.3830G>A (p.Arg1277His)) which have been reported in one proband in one publication (PMID: 24234652) are included in this curation. The mechanism of pathogenicity is reported to be biallelic loss of function, inhibiting LRP4’s affinity for MuSK and agrin. This gene-disease relationship is also supported by an animal model, expression studies, in vitro functional assays, and biochemical function (PMIDs: 18957220, 24234652, 25319686). Conditional knockdown of Lrp4 in mice displayed progressive loss of muscle mass and strength, scoliosis, and ultimately death, consistent with a myasthenic phenotype (PMID: 25319686). Artificially engineered variants at the same functional domain as those observed in the proband (3rd β-propeller domain) compromised agrin-mediated upregulation of MuSK signaling (PMID: 24234652). The expression of LRP4 in myotubes and concentration at the neuromuscular junction as well as its role in attenuating neuronal agrin binding, MuSK activation, and induction of AChR clustering in muscle cells support this gene-disease relationship (PMID: 18957220). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 04.21.2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014578
Submitter: Genomics England PanelApp
Inheritance Pattern: SD
Disease ID:MONDO:0013679
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013679
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014578
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; 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: In Myasthenic syndrome, congenital, treatment with cholinesterase inhibitor was not effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LRP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002334.4. 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 | 1 | 16 | 372 | 3 | 392 | |
| missense | 4 | 13 | 677 | 21 | 2 | 717 |
| nonsense | 7 | 5 | 5 | 17 | ||
| start loss | 0 | |||||
| frameshift | 5 | 6 | 6 | 17 | ||
| splice donor/acceptor (+/-2bp) | 2 | 10 | 9 | 21 | ||
| Total | 19 | 34 | 713 | 393 | 5 | 1164 |
Highest pathogenic variant AF is 0.000019232511
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002325.2 | 38 | MANE Select | |
| Ensembl | ENSP00000367888.1 | 38 | MANE Select | |
| Ensembl | ENSP00000434763.1 | 4 | Standard | |
| Ensembl | ENSP00000528317.1 | 35 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lrp4 | Danio rerio | Structure: muscle Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Extracellular matrix organization
- ECM proteoglycans
Biological Process
- kidney development
- hair follicle development
- endocytosis
- dorsal/ventral pattern formation
- proximal/distal pattern formation
Molecular Function
- calcium ion binding
- protein binding
- receptor tyrosine kinase binding
- apolipoprotein binding
- protein homodimerization activity
Cellular Component
- plasma membrane
- cell surface
- postsynaptic density
- integral component of membrane
- dendrite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378623
- Coding exons
- 38
- Length
- 61775
- Individuals with no LoFs
- 125683
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125748
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.06 | 832 | 1.12e+3 | 0.742 | 0.0000764 | 12584 |
| Missense (PolyPhen) | 213 | 381.29 | 0.55863 | 4199 | ||
| Synonymous | -0.313 | 439 | 431 | 1.02 | 0.0000286 | 3673 |
| Loss of Function | 6.36 | 30 | 97.9 | 0.307 | 0.00000554 | 1052 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00034 | 0.00033 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mediates SOST-dependent inhibition of bone formation. Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling. Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN- induced phosphorylation of MUSK, the kinase of the complex. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes. May play an essential role in the process of digit differentiation (By similarity). {ECO:0000250|UniProtKB:Q8VI56, ECO:0000269|PubMed:20381006, ECO:0000269|PubMed:21471202}.;
- Disease
- DISEASE: Sclerosteosis 2 (SOST2) [MIM:614305]: A sclerosing bone dysplasia characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. {ECO:0000269|PubMed:21471202, ECO:0000269|PubMed:24234652}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 17 (CMS17) [MIM:616304]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. {ECO:0000269|PubMed:24234652}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.170
Intolerance Scores
- LoFtool
- 0.0317
- RVIS EVS
- -1.33
- RVIS percentile EVS
- 4.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |