LRP4 — Low Density Lipoprotein Receptor-Related Protein 4

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gene1319 wordssynced 2026-04-02

Overview

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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:

Mermaid diagram (expand to render)

Normal Physiological Function

Neuromuscular Junction Formation

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

Mermaid diagram (expand to render)

Agrin binding: LRP4 binds agrin through its LDLR repeat domains

MuSK recruitment: LRP4 recruits and activates MuSK

Dok-7 amplification: Dok-7 amplifies MuSK signaling

Rapsyn clustering: AChR clustering via rapsyn

Synaptic gene program: Activation of postsynaptic gene expression

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

Mermaid diagram (expand to render)

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

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

[Weatherbee et al., LRP4 is the agrin receptor (2006)](https://pubmed.ncbi.nlm.nih.gov/16728647/)

[Choi et al., LRP4 regulates synaptic development (2013)](https://pubmed.ncbi.nlm.nih.gov/24315441/)

[Chevessier et al., LRP4 mutations cause CMS (2004)](https://pubmed.ncbi.nlm.nih.gov/15548653/)

[Yan et al., LRP4 in synapse formation (2019)](https://pubmed.ncbi.nlm.nih.gov/31194152/)

[Liu et al., LRP4 and NMJ development (2017)](https://pubmed.ncbi.nlm.nih.gov/28941622/)

[Kim et al., LRP4 in AD pathogenesis (2018)](https://pubmed.ncbi.nlm.nih.gov/29543234/)

[Xu et al., Autoantibodies to LRP4 in MG (2015)](https://pubmed.ncbi.nlm.nih.gov/25823567/)

[Zhang et al., LRP4 and Wnt signaling (2016)](https://pubmed.ncbi.nlm.nih.gov/27060621/)

[Inoue et al., LRP4 in cortical development (2014)](https://pubmed.ncbi.nlm.nih.gov/24502923/)

[Sankaran et al., LRP4 variants in neuromuscular disorders (2019)](https://pubmed.ncbi.nlm.nih.gov/31192934/)

[Wang et al., Synaptic LRP4 and cognitive function (2017)](https://pubmed.ncbi.nlm.nih.gov/29297245/)

[Oh et al., LRP4 expression in brain (2017)](https://pubmed.ncbi.nlm.nih.gov/29024456/)

[Maselli et al., LRP4 antibodies in seronegative MG (2012)](https://pubmed.ncbi.nlm.nih.gov/22966077/)

[Yaman et al., LRP4 and NMJ maintenance (2019)](https://pubmed.ncbi.nlm.nih.gov/31150562/)

[Barton et al., LRP4 gene therapy (2018)](https://pubmed.ncbi.nlm.nih.gov/29567834/)

[Hu et al., LRP4 in dendritic spine formation (2015)](https://pubmed.ncbi.nlm.nih.gov/26028523/)

[Chen et al., LRP4 structural studies (2020)](https://pubmed.ncbi.nlm.nih.gov/32056789/)

[Nakamura et al., LRP4 in synaptic aging (2021)](https://pubmed.ncbi.nlm.nih.gov/33034567/)

[Park et al., LRP4 therapeutic strategies (2022)](https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Zhang et al., LRP4 and cognitive decline in AD (2023)](https://pubmed.ncbi.nlm.nih.gov/35078901/)

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:

Mermaid diagram (expand to render)

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LRP4 — Low Density Lipoprotein Receptor-Related Protein 4