Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation

TL;DR

This study finds rare genetic changes in the LAR receptor that disrupt its function in brain cell connections, potentially linking to psychiatric disorders.

Contribution

The study identifies and characterizes rare missense variants in LAR that impair its synaptic adhesion and function.

Findings

Rare missense variants in LAR destabilize the extracellular domain and increase proteolytic cleavage.

Three variants disrupt the LAR:NGL-3 interaction, leading to loss of transcellular adhesion and synaptogenic effects.

Overexpression of two variants alters neuronal morphology, indicating broad functional consequences.

Abstract

The leukocyte common antigen related receptor (LAR) is a member of the LAR receptor protein tyrosine phosphatase (RPTP) family of synaptic adhesion molecules that contribute to the proper alignment and specialization of synaptic connections in the mammalian brain. LAR-RPTP members have been genetically associated with neuropsychiatric disorders, but the molecular consequences of genetic perturbations of LAR remain unstudied. Using exome sequencing data from psychiatric patients and controls, we identify rare missense variants of LAR that render the extracellular domain (ECD) unstable and susceptible to proteolytic cleavage. Using recombinant and cellular systems, we describe three variants that cause disruption of the LAR:NGL-3 interaction, which results in loss of transcellular adhesion and synaptogenic effects. Furthermore, we show that overexpression of two of these variants elicit altered morphological phenotypes in an imaging-based morphological profiling assay compared to wild type LAR, suggesting that destabilization of the LAR ECD has broad effects on LAR function. In conclusion, our study identifies three rare, missense variants in LAR that could provide insights into LAR involvement with psychiatric pathobiology.

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