Relevance to Autism

Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2 10(-5)). (Ionita-Laza et al., 2012). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (Iossifov et al., 2012).

Molecular Function

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.

External Links

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