De novo missense variants in the LRP1 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (DeRubeis et al., 2014; Iossifov et al., 2014). Whole-exome sequencing of 20 high-functioning autism families in Torrico et al., 2019 identified a de novo splice-site variant in LRP1 that resulted in in-frame skipping of exon 29 and reduced cytokine expression in proband-derived immortalized lymphocyte cell lines. Torrico et al., 2019 also demonstrated that de novo variants in LRP1 are associated with ASD (P=0.039) and schizophrenia (P=0.008), common variants in LRP1 show gene-based association in schizophrenia (P=6.6E-07) and in a meta-analysis across seven psychiatric disorders (P=1.2E-05), and LRP1 exhibits an increased burden of ultra-rare pathogenic variants in a cohort of ASD probands from the ARRA Autism Sequencing Collaboration compared to controls (35 variants in 1778 ASD probands vs. 64 variants in 7875 controls; P-value of 1.2E-05).
Molecular Function
This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
