LRP4

LDL receptor related protein 4

2 disorders 1 untyped 1 causative 11p11.2 gene with protein product

HGNC:6696 Monarch NCBI Gene 4038 ENSG00000134569 UniProt O75096 OMIM 604270

Aliases: MEGF7, CLSS, LRP-4, SOST2.

Normal function · from ai-gene-review (O75096, commit 79fe13b38970) · AI-generated, not KB evidence

LRP4 is a 1,905-residue type-I cell-surface receptor with a large extracellular LDL-receptor-family repeat region, one transmembrane helix, and a cytoplasmic tail. At the neuromuscular junction, its ectodomain binds neuronal AGRIN and MuSK and assembles them into a signaling complex that activates MuSK and promotes acetylcholine-receptor clustering and synapse formation. In osteoblast-lineage cells, LRP4 directly binds the secreted inhibitor sclerostin and facilitates its suppression of canonical Wnt signaling and bone formation. Human variants that perturb different surfaces of the third beta-propeller selectively disrupt these neuromuscular or bone-regulatory functions, causing congenital myasthenic syndrome, Cenani-Lenz syndactyly syndrome, or sclerosteosis-like bone overgrowth.

At the skeletal-muscle neuromuscular junction, LRP4 functions as the extracellular coreceptor that binds neuronal AGRIN and MuSK and brings them into a ternary signaling complex. This enables AGRIN-dependent MuSK activation, acetylcholine-receptor clustering, and coordinated pre- and postsynaptic assembly. Mammalian cell and muscle experiments establish the mechanism, while a human extracellular-fragment cryo-EM structure directly resolves the 1:1:1 complex and human congenital-myasthenia variants impair AGRIN and MuSK binding. The evidence does not make LRP4 a kinase or establish that its cytoplasmic tail supplies the catalytic signal.

molecular function: coreceptor activity · directly involved in: synaptic assembly at neuromuscular junction; positive regulation of skeletal muscle acetylcholine-gated channel clustering · locations: neuromuscular junction; synaptic membrane

In osteoblast-lineage cells, plasma-membrane LRP4 binds sclerostin and acts as a facilitator/coreceptor for its inhibition of canonical Wnt signaling. Direct recombinant-protein binding, LRP4 overexpression and knockdown, and human bone-overgrowth variants support this pathway. Mouse Lrp4-DKK1 and bone phenotypes provide additional in-vivo context, but the direct human evidence is strongest for sclerostin and should not be generalized to every Wnt antagonist or LDLR-family ligand.

molecular function: coreceptor activity · directly involved in: negative regulation of canonical Wnt signaling pathway · locations: plasma membrane

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Sclerosteosis	causative germline	mechanism: Impaired Sclerostin Action at LRP4 subtype: LRP4-related Sclerosteosis scoped to subtype: LRP4-related Sclerosteosis
Congenital Myasthenic Syndrome	untyped Causal	mechanism: Postsynaptic AChR Deficiency, Kinetic Defect, and Impaired Clustering subtype: CMS17 scoped to subtype: CMS17

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
Cenani-Lenz syndactyly syndrome MONDO:0008931	AR	Definitive 2023-04-21	no dismech entry
congenital myasthenic syndrome 17 MONDO:0014578	AR	Limited 2023-04-21	Congenital Myasthenic Syndrome untyped

Mechanism modules · computed from kb/

neuromuscular_transmission_failure via Congenital Myasthenic Syndrome

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.