LRP2

Chr 2AR

LDL receptor related protein 2

Also known as: DBS, GP330, LRP-2

NCBI Gene: 4036 ENSG00000081479 UniProt: P98164 OMIM: 600073

LRP2 encodes megalin, a multiligand endocytic receptor that mediates cellular uptake of diverse molecules including lipoproteins, vitamins, hormones, and morphogens like sonic hedgehog across multiple tissues, particularly absorptive epithelia. Mutations cause Donnai-Barrow syndrome, an autosomal recessive disorder affecting craniofacial development, hearing, vision, and intellectual development. The gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its critical role in development and cellular homeostasis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Donnai-Barrow syndromeMIM #222448

Clinical highlights

Gene-disease validity (ClinGen)

congenital heart disease · ARNo Known Disease Relationshipno established gene-disease relationship

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — LRP2