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.

1. 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
2. LRP4 c.2552C>G (p.(T851R) variant was identified in the family with Chiari malformation type 1. PMID: 28513615
3. A novel splice variant in LRP4 (c.316+1G > A) segregated with Cenani-Lenz syndactyly phenotype in a five generations family. PMID: 28559208
4. LRP4 mutations alter Wnt/beta catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. PMID: 20381006
5. the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. PMID: 26751728
6. 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
7. 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
8. LRP4 is essential for maintaining the structural and functional activity of the neuromuscular junction. PMID: 25319686
9. 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
10. [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
11. 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
12. Cenani-Lenz syndrome in a large Pakistani pedigree is associated with a novel LRP4 missense mutation. PMID: 23664847
13. Data conclude that common variation in the LRP4 gene determines hip and whole body BMD PMID: 23321396
14. The roles of LRP4 in muscle fibers and motoneurons in neuromuscular junction formation have been dissected by cell-specific mutation. PMID: 22794264
15. 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
16. Lrp4 is a cis-acting ligand for MuSK PMID: 21969364
17. 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
18. The present studies suggest that LRP10 may play a significant role in the brain physiology other than lipoprotein metabolism. PMID: 20005200

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Cenani-Lenz syndactyly syndrome (CLSS); Sclerosteosis 2 (SOST2); Myasthenic syndrome, congenital, 17 (CMS17)

Cell membrane; Single-pass type I membrane protein.

LDLR family

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

HGNC: 6696

OMIM: 212780

KEGG: hsa:4038

STRING: 9606.ENSP00000367888

UniGene: Hs.4930