LRP4

Summary

LRP4 (LDL receptor related protein 4, HGNC:6696) is a protein-coding gene on chromosome 11p11.2, encoding Low-density lipoprotein receptor-related protein 4 (O75096). Mediates SOST-dependent inhibition of bone formation.

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.

Source: NCBI Gene 4038 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Cenani-Lenz syndactyly syndrome (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 1,503 total — 20 pathogenic, 25 likely-pathogenic
• MANE Select transcript: NM_002334

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6696
Approved symbol	LRP4
Name	LDL receptor related protein 4
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MEGF7, CLSS, LRP-4, SOST2
Ensembl gene	ENSG00000134569
Ensembl biotype	protein_coding
OMIM	604270
Entrez	4038

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 retained_intron

ENST00000378623, ENST00000527656, ENST00000529604, ENST00000529921, ENST00000534404, ENST00000858258

RefSeq mRNA: 1 — MANE Select: NM_002334 NM_002334

CCDS: CCDS31478

Canonical transcript exons

ENST00000378623 — 38 exons

Exon	Start	End
ENSE00000473384	46876744	46876830
ENSE00000473385	46876466	46876637
ENSE00000473386	46875804	46875966
ENSE00000473389	46873375	46873593
ENSE00000712634	46877199	46877339
ENSE00000712648	46875456	46875681
ENSE00000712651	46874800	46875103
ENSE00000712659	46868988	46869132
ENSE00000712660	46868600	46868713
ENSE00000712661	46867979	46868114
ENSE00000921202	46856717	46859315
ENSE00000921203	46862606	46862747
ENSE00000921204	46864448	46864535
ENSE00000921205	46865119	46865186
ENSE00001097958	46890277	46890494
ENSE00001097963	46894589	46894819
ENSE00001097965	46895884	46896018
ENSE00001097966	46881702	46881903
ENSE00001097970	46889944	46890120
ENSE00001097971	46892973	46893129
ENSE00001097975	46895166	46895291
ENSE00001097977	46879126	46879315
ENSE00001131498	46878907	46879038
ENSE00001131514	46883871	46883976
ENSE00001131799	46886325	46886533
ENSE00001131807	46889411	46889533
ENSE00001222472	46896210	46896335
ENSE00001404504	46918328	46918550
ENSE00001414257	46900262	46900378
ENSE00001416796	46902783	46902929
ENSE00001422125	46899863	46899976
ENSE00001423248	46896869	46896994
ENSE00001426655	46898904	46899032
ENSE00001428740	46898558	46898677
ENSE00003500235	46886091	46886172
ENSE00003635876	46873100	46873234
ENSE00003653364	46871525	46871633
ENSE00003790055	46899387	46899503

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9792 / max 126.9703, expressed in 920 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119546	3.9792	920

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.67	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.49	gold quality
medial globus pallidus	UBERON:0002477	95.74	gold quality
putamen	UBERON:0001874	95.47	gold quality
globus pallidus	UBERON:0001875	95.22	gold quality
caudate nucleus	UBERON:0001873	95.18	gold quality
skin of leg	UBERON:0001511	94.32	gold quality
skin of abdomen	UBERON:0001416	94.14	gold quality
inferior olivary complex	UBERON:0002127	94.04	gold quality
nucleus accumbens	UBERON:0001882	93.90	gold quality
amygdala	UBERON:0001876	93.80	gold quality
CA1 field of hippocampus	UBERON:0003881	93.41	gold quality
zone of skin	UBERON:0000014	93.11	gold quality
upper arm skin	UBERON:0004263	92.43	gold quality
right frontal lobe	UBERON:0002810	92.38	gold quality
ganglionic eminence	UBERON:0004023	92.30	gold quality
skin of hip	UBERON:0001554	92.19	gold quality
Ammon’s horn	UBERON:0001954	92.10	gold quality
temporal lobe	UBERON:0001871	92.03	gold quality
lateral globus pallidus	UBERON:0002476	91.90	gold quality
upper leg skin	UBERON:0004262	91.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.17	gold quality
tibia	UBERON:0000979	91.14	gold quality
telencephalon	UBERON:0001893	90.80	gold quality
substantia nigra	UBERON:0002038	90.62	gold quality
hypothalamus	UBERON:0001898	90.45	gold quality
midbrain	UBERON:0001891	90.01	gold quality
entorhinal cortex	UBERON:0002728	89.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.58	gold quality
primary visual cortex	UBERON:0002436	89.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.44
E-MTAB-6678	no	2.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting LRP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 36)

• The present studies suggest that LRP10 may play a significant role in the brain physiology other than lipoprotein metabolism. (PMID:20005200)
• LRP4 mutations alter Wnt/beta catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. (PMID:20381006)
• the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone. (PMID:21471202)
• Data suggest that LRP4 and interaction between LRP4 and genes in the Wnt and BMP signaling pathways modulate bone phenotypes including peak bone mass and fracture, the clinical endpoint of osteoporosis. (PMID:21645651)
• Lrp4 is a cis-acting ligand for MuSK (PMID:21969364)
• The roles of LRP4 in muscle fibers and motoneurons in neuromuscular junction formation have been dissected by cell-specific mutation. (PMID:22794264)
• Data conclude that common variation in the LRP4 gene determines hip and whole body BMD (PMID:23321396)
• Cenani-Lenz syndrome in a large Pakistani pedigree is associated with a novel LRP4 missense mutation. (PMID:23664847)
• LRP4 is a new CMS disease gene and the 3rd beta propeller domain of LRP4 mediates two signaling pathways in a position-specific manner. (PMID:24234652)
• MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters (PMID:24244707)
• pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. (PMID:24297891)
• [review] Autoantibodies against LRP4 differentially alter neuromuscular transmission, demonstrating how myasthenia gravis can be classified according to the profile of the antibodies; management of myasthenia gravis patients can be adapted accordingly. (PMID:24530233)
• study presents 2 sibling fetuses with a prenatal lethal presentation of mesomelic limb reductions, oligosyndactyly, genitourinary malformation and compound heterozygosity for 2 novel truncating mutations in LRP4 (PMID:24924585)
• LRP4 is essential for maintaining the structural and functional activity of the neuromuscular junction. (PMID:25319686)
• the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. (PMID:26751728)
• LRP4 c.2552C>G (p.(T851R) variant was identified in the family with Chiari malformation type 1. (PMID:28513615)
• A novel splice variant in LRP4 (c.316+1G > A) segregated with Cenani-Lenz syndactyly phenotype in a five generations family. (PMID:28559208)
• These results suggest that variants in the fourth beta-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants. (PMID:29524275)
• In vitro experiments demonstrated that LRP4 downregulation significantly inhibited the colony formation, proliferation, migration, and invasion of the three papillary thyroid cancer cell lines. (PMID:29885843)
• The results showed that LRP4 suppressed both Wnt/beta-Catenin and Notch signaling pathways, and these activities were perturbed either by LRP4 missense mutations or by a knockdown of LRP4. (PMID:30327840)
• Cenani-Lenz (C-L) syndrome-like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1-FMN1 locus, as well as FMN1 mutations. (PMID:30569497)
• Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family. (PMID:31750994)
• A novel biallelic splice-site variant in the LRP4 gene causes sclerosteosis 2. (PMID:32286743)
• A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Abeta Clearance. (PMID:32457076)
• LRP4 promotes migration and invasion of gastric cancer under the regulation of microRNA-140-5p. (PMID:32675391)
• Lethal Cenani Lenz syndrome in two consecutive pregnancies: Further extension of phenotype from Maldives. (PMID:33179409)
• The VWF/LRP4/alphaVbeta3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells. (PMID:33576766)
• Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome. (PMID:34857885)
• Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third beta-Propeller Domain Can Cause Sclerosteosis. (PMID:35052419)
• Knockdown of long noncoding RNA HUMT inhibits the proliferation and metastasis by regulating miR-455-5p/LRP4 axis in hepatocellular carcinoma. (PMID:35293286)
• Correlation between BTG3, CASP9 and LRP4 single-nucleotide polymorphisms and susceptibility to papillary thyroid carcinoma. (PMID:35362324)
• The collagen ColQ binds to LRP4 and regulates the activation of the Muscle-Specific Kinase-LRP4 receptor complex by agrin at the neuromuscular junction. (PMID:37356721)
• A variant in the LDL receptor-related protein encoding gene LRP4 underlying polydactyly and phalangeal synostosis in a family of Pakistani origin. (PMID:37563890)
• LRP4 mutations, dental anomalies, and oral exostoses. (PMID:38013205)
• LRP4-related signalling pathways and their regulatory role in neurological diseases. (PMID:38065285)
• LRP4 site-specific variants in the third beta-propeller domain causes congenital myasthenic syndrome type 17. (PMID:38101565)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrp4	ENSDARG00000116353
mus_musculus	Lrp4	ENSMUSG00000027253
rattus_norvegicus	Lrp4	ENSRNOG00000015285
drosophila_melanogaster	arr	FBGN0000119

Paralogs (14): LRP6 (ENSG00000070018), LRP2 (ENSG00000081479), NID2 (ENSG00000087303), NID1 (ENSG00000116962), LRP1 (ENSG00000123384), LDLR (ENSG00000130164), LRP3 (ENSG00000130881), EGF (ENSG00000138798), LRP12 (ENSG00000147650), VLDLR (ENSG00000147852), LRP8 (ENSG00000157193), LRP5 (ENSG00000162337), LRP1B (ENSG00000168702), LRP10 (ENSG00000197324)

Protein

Protein identifiers

Low-density lipoprotein receptor-related protein 4 — O75096 (reviewed: O75096)

Alternative names: Multiple epidermal growth factor-like domains 7

All UniProt accessions (2): E9PNJ5, O75096

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Homooligomer. Interacts with MUSK; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK. Interacts (via the extracellular domain) with SOST; the interaction facilitates the inhibition of Wnt signaling. Interacts with MESD; the interaction promotes glycosylation of LRP4 and its cell-surface expression.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in bone; present in osteoblasts and osteocytes. No expression is observed in osteoclast. Expressed in several regions of the brain.

Disease relevance. Cenani-Lenz syndactyly syndrome (CLSS) [MIM:212780] A congenital malformation syndrome defined as complete and complex syndactyly of the hands combined with malformations of the forearm bones and similar manifestations in the lower limbs. It is characterized by fusion and disorganization of metacarpal and phalangeal bones, radius and ulnar shortening, radioulnar synostosis, and severe syndactyly of hands and feet. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the LDLR family.

RefSeq proteins (1): NP_002325* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR026823	cEGF	Domain
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR051221	LDLR-related	Family

Pfam: PF00057, PF00058, PF12662, PF14670

UniProt features (105 total): disulfide bond 33, repeat 20, sequence variant 17, domain 11, glycosylation site 7, mutagenesis site 4, sequence conflict 3, topological domain 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8S9P	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75096-F1	77.57	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (33): 27–44, 34–57, 51–66, 71–83, 78–96, 90–105, 110–122, 117–135, 129–143, 148–160, 155–173, 167–182, 191–203, 198–216, 210–225, 231–243, 238–256, 250–265, 270–282, 277–295 …

Glycosylation sites (7): 264, 498, 719, 901, 1077, 1415, 1467

Mutagenesis-validated functional residues (4):

Position	Phenotype
1256	compromises wnt-suppressive activity.
1287	compromises agrn-mediated up-regulation of musk signaling.
1214	compromises wnt-suppressive activity.
1252	compromises agrn-mediated up-regulation of musk signaling.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3000178	ECM proteoglycans
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 555 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GCM_MAP4K4, GOBP_EPITHELIUM_DEVELOPMENT, ACTACCT_MIR196A_MIR196B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS

GO Biological Process (31): kidney development (GO:0001822), hair follicle development (GO:0001942), endocytosis (GO:0006897), enzyme-linked receptor protein signaling pathway (GO:0007167), dorsal/ventral pattern formation (GO:0009953), proximal/distal pattern formation (GO:0009954), Wnt signaling pathway (GO:0016055), Rac protein signal transduction (GO:0016601), negative regulation of ossification (GO:0030279), positive regulation of Rac protein signal transduction (GO:0035022), odontogenesis of dentin-containing tooth (GO:0042475), embryonic digit morphogenesis (GO:0042733), generation of neurons (GO:0048699), dendrite morphogenesis (GO:0048813), negative regulation of axonogenesis (GO:0050771), synapse organization (GO:0050808), synaptic assembly at neuromuscular junction (GO:0051124), limb development (GO:0060173), skeletal muscle acetylcholine-gated channel clustering (GO:0071340), negative regulation of canonical Wnt signaling pathway (GO:0090090), postsynaptic membrane assembly (GO:0097104), presynaptic membrane assembly (GO:0097105), regulation of postsynapse assembly (GO:0150052), amyloid-beta clearance by cellular catabolic process (GO:0150094), positive regulation of presynaptic membrane organization (GO:1901631), positive regulation of skeletal muscle acetylcholine-gated channel clustering (GO:1904395), intracellular protein localization (GO:0008104), cell differentiation (GO:0030154), embryonic limb morphogenesis (GO:0030326), receptor clustering (GO:0043113), system development (GO:0048731)

GO Molecular Function (7): calcium ion binding (GO:0005509), coreceptor activity (GO:0015026), receptor tyrosine kinase binding (GO:0030971), apolipoprotein binding (GO:0034185), protein homodimerization activity (GO:0042803), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (10): plasma membrane (GO:0005886), cell surface (GO:0009986), postsynaptic density (GO:0014069), dendrite (GO:0030425), neuromuscular junction (GO:0031594), neuronal cell body (GO:0043025), plasma membrane raft (GO:0044853), synaptic membrane (GO:0097060), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	2
regionalization	2
neuromuscular junction development	2
protein binding	2
cellular anatomical structure	2
synapse	2
plasma membrane region	2
animal organ development	1
renal system development	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
small GTPase-mediated signal transduction	1
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
odontogenesis	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
neurogenesis	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axonogenesis	1
negative regulation of neuron projection development	1
negative regulation of neurogenesis	1
regulation of axonogenesis	1
cell junction organization	1
synapse assembly	1
developmental growth	1
appendage development	1
postsynaptic membrane organization	1
receptor clustering	1

Protein interactions and networks

STRING

922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRP4	MUSK	O15146	994
LRP4	AGRN	O00468	994
LRP4	RIOX2	Q8IUF8	783
LRP4	APP	P05067	762
LRP4	WNT7A	O00755	736
LRP4	DOK7	Q18PE1	699
LRP4	RAPSN	Q13702	632
LRP4	LMX1B	O60663	620
LRP4	TMEM230	Q96A57	512
LRP4	LRP11	Q86VZ4	505
LRP4	COLQ	Q9Y215	489
LRP4	BMP4	P12644	487
LRP4	SPON1	Q9HCB6	478
LRP4	FGF8	P55075	477
LRP4	BMP2	P12643	470

IntAct

212 interactions, top by confidence:

A	B	Type	Score
SOST	LRP4	psi-mi:“MI:0914”(association)	0.790
LRP4	SOST	psi-mi:“MI:0407”(direct interaction)	0.790
SOST	LRP4	psi-mi:“MI:0407”(direct interaction)	0.790
SOST	LRP4	psi-mi:“MI:0915”(physical association)	0.790
WDR20	PHLPP1	psi-mi:“MI:0914”(association)	0.670
LRP4	WHRN	psi-mi:“MI:0915”(physical association)	0.590
LRP4	WHRN	psi-mi:“MI:0407”(direct interaction)	0.590
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
ZNF398	LRP4	psi-mi:“MI:0914”(association)	0.530
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
ZNF331	USP9Y	psi-mi:“MI:0914”(association)	0.530
ZNF354C	IPO8	psi-mi:“MI:0914”(association)	0.530
LRPAP1	LRP4	psi-mi:“MI:0914”(association)	0.530
GDF10	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF816	LRP4	psi-mi:“MI:0914”(association)	0.530
ZSCAN26	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF621	LRP4	psi-mi:“MI:0914”(association)	0.530
BEND7	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF563	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF556	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF224	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF214	LRP4	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (116): LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP4 (Affinity Capture-MS)

ESM2 similar proteins: A1A5Y0, A2ARV4, C0HL13, G3V928, O75096, P01130, P01131, P01132, P01133, P07522, P20063, P35950, P35951, P35952, P35953, P58459, P59384, P59511, P97607, P98155, P98156, P98157, P98158, P98164, P98165, P98166, Q00968, Q07954, Q14114, Q1EHB3, Q28832, Q62918, Q63415, Q68SA9, Q8TE57, Q8VI56, Q90Y57, Q91WP0, Q91ZX7, Q924X6

Diamond homologs: A2AJ76, A2ARV4, A4QPB2, A8WGB1, B3EWY9, B3NBB6, B4HVU2, B4QMF4, C0HL13, G3V928, O42182, O73775, O75096, O75197, O75581, O88307, O88572, O89103, P01131, P01132, P01133, P07225, P07522, P0DSP1, P10493, P14543, P15306, P20063, P23142, P27590, P34576, P35950, P35951, P35952, P35953, P48960, P98095, P98155, P98156, P98157

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SDF2L1	“up-regulates activity”	LRP4	binding
AGRN	“up-regulates activity”	LRP4	binding
LRP4	“up-regulates activity”	MUSK	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Dopamine Neurotransmitter Release Cycle	6	30.4×	4e-06
Ras activation upon Ca2+ influx through NMDA receptor	5	29.1×	5e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	27.8×	5e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	27.8×	5e-05
Assembly and cell surface presentation of NMDA receptors	10	25.9×	1e-09
Long-term potentiation	5	24.3×	8e-05
Neurotransmitter release cycle	5	22.4×	1e-04
Neurexins and neuroligins	10	20.1×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	40.9×	2e-11
receptor clustering	8	35.2×	1e-08
protein localization to synapse	5	27.0×	1e-04
neurotransmitter secretion	5	24.7×	1e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	6	20.9×	5e-05
establishment of cell polarity	5	13.5×	2e-03
mitotic spindle organization	5	9.6×	7e-03
protein-containing complex assembly	8	6.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1503 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	25
Uncertain significance	734
Likely benign	538
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323250	NM_002334.4(LRP4):c.2830C>T (p.Gln944Ter)	Pathogenic
1393202	NM_002334.4(LRP4):c.2260C>T (p.Arg754Ter)	Pathogenic
2112258	NM_002334.4(LRP4):c.2498del (p.Thr833fs)	Pathogenic
2921833	NM_002334.4(LRP4):c.1850del (p.Ala617fs)	Pathogenic
2945597	NM_002334.4(LRP4):c.4400dup (p.Asn1467fs)	Pathogenic
2950364	NM_002334.4(LRP4):c.1123_1126dup (p.Val376fs)	Pathogenic
3756432	NM_002334.4(LRP4):c.5215del (p.Val1739fs)	Pathogenic
3756686	NM_002334.4(LRP4):c.3898C>T (p.Gln1300Ter)	Pathogenic
3764559	NM_002334.4(LRP4):c.2613-2A>T	Pathogenic
428601	NM_002334.4(LRP4):c.316+1G>A	Pathogenic
4783116	NM_002334.4(LRP4):c.2656C>T (p.Arg886Ter)	Pathogenic
4785456	NM_002334.4(LRP4):c.3549G>A (p.Trp1183Ter)	Pathogenic
4794477	NM_002334.4(LRP4):c.5308C>T (p.Arg1770Ter)	Pathogenic
5686	NM_002334.4(LRP4):c.1585G>A (p.Asp529Asn)	Pathogenic
5688	NM_002334.4(LRP4):c.4959C>G (p.Gly1653=)	Pathogenic
5690	NM_002334.4(LRP4):c.479G>A (p.Cys160Tyr)	Pathogenic
5691	NM_002334.4(LRP4):c.1345G>A (p.Asp449Asn)	Pathogenic
5692	NM_002334.4(LRP4):c.1381A>C (p.Thr461Pro)	Pathogenic
5693	NM_002334.4(LRP4):c.200-9G>A	Pathogenic
576661	NM_002334.4(LRP4):c.2866G>T (p.Glu956Ter)	Pathogenic
1179057	NM_002334.4(LRP4):c.1560G>A (p.Trp520Ter)	Likely pathogenic
1179202	NM_002334.4(LRP4):c.1184-1G>A	Likely pathogenic
2119457	NM_002334.4(LRP4):c.3699+1G>A	Likely pathogenic
2687873	NM_002334.4(LRP4):c.2814+1G>A	Likely pathogenic
2690639	NM_002334.4(LRP4):c.4225_4226insC (p.Ile1409fs)	Likely pathogenic
2925899	NM_002334.4(LRP4):c.1184-2A>G	Likely pathogenic
2937965	NM_002334.4(LRP4):c.898G>A (p.Asp300Asn)	Likely pathogenic
2948041	NM_002334.4(LRP4):c.2507-1G>A	Likely pathogenic
3033752	NM_002334.4(LRP4):c.4230-2A>T	Likely pathogenic
3344039	NM_002334.4(LRP4):c.317-1G>C	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

12641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:46869083:C:G	R1581P	1.000
11:46869103:C:A	W1574C	1.000
11:46869103:C:G	W1574C	1.000
11:46869114:A:G	W1571R	1.000
11:46869114:A:T	W1571R	1.000
11:46871537:A:C	F1560L	1.000
11:46871537:A:T	F1560L	1.000
11:46871539:A:G	F1560L	1.000
11:46871604:C:G	R1538P	1.000
11:46871619:T:A	D1533V	1.000
11:46871620:C:A	D1533Y	1.000
11:46871620:C:G	D1533H	1.000
11:46871626:A:G	W1531R	1.000
11:46871626:A:T	W1531R	1.000
11:46873133:G:T	P1517H	1.000
11:46873213:C:A	W1490C	1.000
11:46873213:C:G	W1490C	1.000
11:46873215:A:G	W1490R	1.000
11:46873215:A:T	W1490R	1.000
11:46873224:A:G	W1487R	1.000
11:46873224:A:T	W1487R	1.000
11:46873405:G:T	P1473H	1.000
11:46873528:C:T	G1432E	1.000
11:46873529:C:A	G1432W	1.000
11:46875824:A:G	W1227R	1.000
11:46875824:A:T	W1227R	1.000
11:46879283:A:C	F949L	1.000
11:46879283:A:T	F949L	1.000
11:46879285:A:G	F949L	1.000
11:46881802:G:T	P905H	1.000

dbSNP variants (sampled 300 via entrez): RS1000008076 (11:46899336 G>A), RS1000086089 (11:46873927 G>A), RS1000127673 (11:46880700 A>C), RS1000217367 (11:46915517 G>A), RS1000308707 (11:46901778 T>C), RS1000315388 (11:46858483 G>A), RS1000354675 (11:46888594 G>A,T), RS1000403271 (11:46887802 G>A), RS1000430920 (11:46895346 C>G), RS1000622212 (11:46918684 C>T), RS1000744964 (11:46878938 G>A), RS1000767592 (11:46893960 C>T), RS1000795235 (11:46893478 A>G), RS1000870936 (11:46867839 C>A,T), RS1000892795 (11:46914420 G>A,T)

Disease associations

OMIM: gene MIM:604270 | disease phenotypes: MIM:212780, MIM:614305, MIM:616304, MIM:156000, MIM:600334, MIM:603689, MIM:607569, MIM:604145, MIM:608807, MIM:611705, MIM:613765, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
Cenani-Lenz syndactyly syndrome	Definitive	Autosomal recessive
congenital myasthenic syndrome 17	Strong	Autosomal recessive
sclerosteosis	Supportive	Autosomal recessive
postsynaptic congenital myasthenic syndrome	Supportive	Autosomal recessive
sclerosteosis 2	Limited	Semidominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Cenani-Lenz syndactyly syndrome	Definitive	AR
congenital myasthenic syndrome 17	Limited	AR

Mondo (15): Cenani-Lenz syndactyly syndrome (MONDO:0008931), sclerosteosis 2 (MONDO:0013679), congenital myasthenic syndrome 17 (MONDO:0014578), epilepsy (MONDO:0005027), Meniere disease (MONDO:0007972), intellectual disability (MONDO:0001071), tibial muscular dystrophy (MONDO:0010870), myopathy, myofibrillar, 9, with early respiratory failure (MONDO:0011362), dilated cardiomyopathy 1G (MONDO:0011400), autosomal recessive limb-girdle muscular dystrophy type 2J (MONDO:0012127), early-onset myopathy with fatal cardiomyopathy (MONDO:0012714), hypertrophic cardiomyopathy 9 (MONDO:0013412), craniosynostosis (MONDO:0015469), sclerosteosis (MONDO:0017838), postsynaptic congenital myasthenic syndrome (MONDO:0020344)

Orphanet (12): Sclerosteosis (Orphanet:3152), Cenani-Lenz syndrome (Orphanet:3258), Congenital myasthenic syndrome (Orphanet:590), Titin-related limb-girdle muscular dystrophy R10 (Orphanet:140922), Familial isolated dilated cardiomyopathy (Orphanet:154), Hereditary myopathy with early respiratory failure (Orphanet:178464), Early-onset myopathy with fatal cardiomyopathy (Orphanet:289377), Distal myopathy with early respiratory muscle involvement (Orphanet:34521), Tibial muscular dystrophy (Orphanet:609), Craniosynostosis (Orphanet:1531), NON RARE IN EUROPE: Menière disease (Orphanet:45360), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008575	Meniere Disease	C09.218.568.217.500
C565824	Cardiomyopathy, Dilated, 1g (supp.)
C566044	Cardiomyopathy, Familial Hypertrophic, 9 (supp.)
C566343	Hereditary Myopathy with Early Respiratory Failure (supp.)
C563854	Muscular Dystrophy, Limb-Girdle, Type 2J (supp.)
C567129	Myopathy, Early-Onset, with Fatal Cardiomyopathy (supp.)
C537525	Sclerosteosis (supp.)
C538150	Syndactyly Cenani Lenz type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation	2
Estradiol	affects cotreatment, increases expression	2
Tretinoin	decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, increases expression	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Ethanol	increases expression	1
Antimycin A	decreases expression	1
Arsenic	affects methylation	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2BC	HAP1 LRP4 (-) 1	Cancer cell line	Male
CVCL_E2BD	HAP1 LRP4 (-) 2	Cancer cell line	Male
CVCL_E2BE	HAP1 LRP4 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy