LRP4 — Low Density Lipoprotein Receptor-Related Protein 4

LRP4 — Low Density Lipoprotein Receptor-Related Protein 4

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">LRP4 — Low Density Lipoprotein Receptor-Related Protein 4</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>LRP4</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Low Density Lipoprotein Receptor-Related Protein 4</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p11.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>4038</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000134538</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NZU0</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604270</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Exon Count</td>
<td>33 exons</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>LRP4</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~195 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>1725 amino acids</td>
</tr>
<tr>
<td class="label">Topology</td>
<td>Type I transmembrane receptor</td>
</tr>
<tr>
<td class="label">Domains</td>
<td>8 LDLR class A repeats, 4 EGF-like repeats, transmembrane, cytoplasmic</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cell membrane (postsynaptic), endosomes</td>
</tr>

LRP4 — Low Density Lipoprotein Receptor-Related Protein 4

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">LRP4 — Low Density Lipoprotein Receptor-Related Protein 4</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>LRP4</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Low Density Lipoprotein Receptor-Related Protein 4</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p11.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>4038</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000134538</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NZU0</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604270</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Exon Count</td>
<td>33 exons</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>LRP4</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~195 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>1725 amino acids</td>
</tr>
<tr>
<td class="label">Topology</td>
<td>Type I transmembrane receptor</td>
</tr>
<tr>
<td class="label">Domains</td>
<td>8 LDLR class A repeats, 4 EGF-like repeats, transmembrane, cytoplasmic</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cell membrane (postsynaptic), endosomes</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Amino Acids</td>
</tr>
<tr>
<td class="label">Signal peptide</td>
<td>1-23</td>
</tr>
<tr>
<td class="label">LDLR repeats</td>
<td>24-714</td>
</tr>
<tr>
<td class="label">EGF-like repeats</td>
<td>715-1035</td>
</tr>
<tr>
<td class="label">Spacer region</td>
<td>1036-1095</td>
</tr>
<tr>
<td class="label">TM domain</td>
<td>1096-1118</td>
</tr>
<tr>
<td class="label">Cytoplasmic</td>
<td>1119-1725</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>LRP4 Expression</td>
</tr>
<tr>
<td class="label">[Hippocampus](/brain-regions/hippocampus)</td>
<td>High</td>
</tr>
<tr>
<td class="label">[Cerebral cortex](/brain-regions/cortex)</td>
<td>High</td>
</tr>
<tr>
<td class="label">[Cerebellum](/brain-regions/cerebellum)</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">[Basal ganglia](/brain-regions/basal-ganglia)</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Antibody Type</td>
<td>Prevalence</td>
</tr>
<tr>
<td class="label">Anti-LRP4 (total)</td>
<td>9-19% of MG</td>
</tr>
<tr>
<td class="label">Anti-LRP4 only</td>
<td>2-5% of MG</td>
</tr>
<tr>
<td class="label">Anti-LRP4 + anti-AChR</td>
<td>7-8% of MG</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Missense</td>
<td>Reduced agrin binding</td>
</tr>
<tr>
<td class="label">Nonsense</td>
<td>Truncated protein</td>
</tr>
<tr>
<td class="label">Splice site</td>
<td>Aberrant splicing</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Agrin fragments</td>
<td>LRP4 activation</td>
</tr>
<tr>
<td class="label">MuSK agonists</td>
<td>Downstream signaling</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>LRP4 expression</td>
</tr>
<tr>
<td class="label">Antibody therapy</td>
<td>Autoantibodies</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Phenotype</td>
</tr>
<tr>
<td class="label">Lrp4-/-</td>
<td>Embry lethal (E13.5-14.5)</td>
</tr>
<tr>
<td class="label">Lrp4flox/flox</td>
<td>Inducible KO</td>
</tr>
<tr>
<td class="label">Lrp4+/-</td>
<td>Viable, mild NMJ defects</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">59 edges</a></td>
</tr>
</table>

LRP4 encodes the Low Density Lipoprotein Receptor-Related Protein 4, a transmembrane receptor that plays critical roles in synapse formation, neuromuscular junction (NMJ) development, and bone metabolism. LRP4 serves as the primary receptor for the neuromuscular junction organizer [agrin](/proteins/agrin), acting in concert with muscle-specific kinase (MuSK) to orchestrate postsynaptic specialization and maintain synaptic integrity. Beyond its well-characterized role at the NMJ, LRP4 is expressed in the central nervous system where it influences dendritic spine formation, synaptic plasticity, and cognitive function. Recent research also implicates LRP4 in Alzheimer's disease pathogenesis through interactions with amyloid precursor protein (APP) and amyloid-beta (Aβ) metabolism. [@kim2018]

The LRP4 gene is located on chromosome 11p11.2 and encodes a 1725-amino acid transmembrane protein belonging to the LDLR family. Pathogenic variants in LRP4 cause congenital myasthenic syndrome (CMS) characterized by fatigable muscle weakness, while autoantibodies against LRP4 are found in a subset of patients with myasthenia gravis. The dual roles of LRP4 in both peripheral neuromuscular transmission and central synaptic function make it a unique factor bridging development, neuromuscular disease, and neurodegeneration. [@weatherbee2006]

Gene Information

Protein Overview

Domain Structure

LRP4 contains multiple functional domains that mediate its diverse interactions:

Normal Physiological Function

Neuromuscular Junction Formation

LRP4 is the critical postsynaptic receptor for agrin, the master organizer of the NMJ: [@liu2017]

Synaptic Function in the CNS

In the central nervous system, LRP4 performs distinct functions: [@yan2019]

• Dendritic spine formation: LRP4 regulates spine morphological development
• Synaptic plasticity: Influences LTP and LTD
• Cognitive function: Required for learning and memory
• APP metabolism: Interacts with amyloid precursor protein processing

Wnt Signaling

LRP4 participates in canonical Wnt signaling during development: [@zhang2016]

• Wnt ligand binding: Can bind Wnt1, Wnt3a, and Wnt10b
• β-catenin regulation: Modulates intracellular β-catenin levels
• Developmental roles: Bone, muscle, and neural development

Brain Expression Pattern

Regional Distribution

Cell-Type Specificity

• Pyramidal neurons: High expression in dendritic trees
• Interneurons: Moderate expression
• Astrocytes: Low expression
• Microglia: Not detected

Role in Neurodegeneration

Alzheimer's Disease

LRP4 has emerged as an important factor in AD pathogenesis: [@kim2018]

APP Interaction

• Binds APP: LRP4 interacts with the amyloid precursor protein
• Alters processing: Influences α-secretase vs. β-secretase cleavage
• Aβ production: Decreased LRP4 reduces Aβ generation
• Synaptic protection: May protect against Aβ-induced dysfunction

Synaptic Function

• Spine loss protection: LRP4 maintains dendritic spines in AD models
• Cognitive decline: Reduced LRP4 correlates with cognitive impairment
• Therapeutic target: LRP4-enhancing strategies being explored

Myasthenia Gravis

Autoantibodies against LRP4 are found in patients with myasthenia gravis: [@maselli2012]

The antibodies likely disrupt LRP4-agrin interactions, impairing NMJ function.

Congenital Myasthenic Syndrome

Biallelic pathogenic variants in LRP4 cause CMS: [@chevessier2004]

Therapeutic Targeting

Current Approaches

Drug Development

• Small molecule LRP4 modulators: Under development
• Peptide agonists: Agrin-derived peptides
• Gene therapy vectors: AAV-Musk promoter constructs

Animal Models

Knockout Models

Transgenic Models

• LRP4 overexpression: Enhanced NMJ size
• Human mutations: Disease modeling
• Conditional CNS KO: Brain-specific analysis

See Also

• [Agrin](/proteins/agrin) — Neuromuscular junction organizer
• [MuSK](/genes/musk) — Muscle-specific kinase
• [AChR](/proteins/ach-receptor) — Acetylcholine receptor
• [Neuromuscular Junction](/mechanisms/neuromuscular-junction) — NMJ biology
• [Synaptic Plasticity](/mechanisms/synaptic-plasticity) — Synapse function
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Neurodegenerative disease
• [Myasthenia Gravis](/diseases/myasthenia-gravis) — Autoimmune NMJ disease

External Links

• [NCBI Gene: LRP4](https://www.ncbi.nlm.nih.gov/gene/4038)
• [UniProt: LRP4](https://www.uniprot.org/uniprot/Q9NZU0)
• [Ensembl: LRP4](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000134538)
• [OMIM: LRP4](https://www.omim.org/entry/604270)
• [GeneCards: LRP4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=LRP4)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving LRP4 — Low Density Lipoprotein Receptor-Related Protein 4 discovered through SciDEX knowledge graph analysis: