LRP2

LDL receptor related protein 2

2 disorders 1 causative 1 untyped 2q31.1 gene with protein product

HGNC:6694 Monarch NCBI Gene 4036 ENSG00000081479 UniProt P98164 OMIM 600073

Aliases: gp330, DBS.

Normal function · from ai-gene-review (P98164, commit 79fe13b38970) · AI-generated, not KB evidence

LRP2, also called megalin, is a 4,655-residue type-I single-pass cargo receptor expressed at the apical surface of absorptive epithelia, especially renal proximal tubules and choroid plexus. Its large LDL-receptor-family ectodomain binds diverse protein, lipoprotein, vitamin-carrier, hormone, and metal-carrier cargos, often in cooperation with cubilin, while cytoplasmic sorting motifs recruit endocytic adaptors. LRP2 enters clathrin-coated carriers, releases cargo in acidic endosomes, and recycles to the cell surface; in specialized epithelia it can also support transcytosis. This receptor cycle underlies renal reclamation and tissue-specific delivery or clearance of extracellular macromolecules. Biallelic human LRP2 variants cause Donnai-Barrow/facio-oculo-acoustico-renal syndrome, consistent with important functions in kidney, brain, eye, ear, and embryonic development.

At the apical plasma membrane of absorptive epithelia, LRP2 functions as a multiligand cargo receptor that couples extracellular cargo binding to clathrin-dependent receptor-mediated endocytosis. Cytoplasmic FXNPXY motifs recruit endocytic adaptors, and the receptor passes through coated carriers and endosomes, where acidic pH drives cargo release before receptor recycling. Direct experiments support uptake of clusterin and survivin, while conserved mammalian studies support additional vitamin-carrier, hormone, protein, and metal-carrier cargos. The cargo repertoire is tissue-specific, and no single ligand explains all LRP2 biology.

molecular function: cargo receptor activity · directly involved in: receptor-mediated endocytosis · locations: apical plasma membrane; clathrin-coated pit; endosome

In choroid-plexus epithelium, LRP2 acts as a cargo receptor for transcytotic delivery across the blood-CSF interface. Mixed rodent and human evidence supports binding of circulating leptin at the epithelial receptor and its transport into brain. This is a specialized epithelial deployment of the LRP2 endocytic cycle; reduced receptor abundance in aging or Alzheimer-disease samples is correlative and does not establish patient-level causality.

molecular function: cargo receptor activity · directly involved in: transcytosis · locations: apical plasma membrane; endosome

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
Congenital Diaphragmatic Hernia	causative
Donnai-Barrow syndrome	untyped Causal biallelic variant	mechanism: LRP2-related megalin endocytic dysfunction diagnosis: LRP2 molecular genetic testing

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
congenital heart disease MONDO:0005453	AR	No Known Disease Relationship 2024-09-09	Congenital Heart Disease not named

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