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

Mathias Kaas; Nicolas Chofflet; Deniz Bicer; Sune Skeldal; Jinjie Duan; Benjamin Feller; Joachim Vilstrup; Rosa Groth; Suganya Sivagurunathan; Hesam Dashti; Jan Skov Pedersen; Thomas Werge; Anders D Børglum; Beth A Cimini; Thouis R Jones; Melina Claussnitzer; Peder Madsen; Hideto Takahashi; Ditte Demontis; Søren Thirup; Simon Glerup

doi:10.1101/2025.02.16.638491

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

Mathias Kaas, Nicolas Chofflet, Deniz Bicer, Sune Skeldal, Jinjie Duan, Benjamin Feller, Joachim Vilstrup, Rosa Groth, Suganya Sivagurunathan, Hesam Dashti, Jan Skov Pedersen, Thomas Werge, Anders D Børglum, Beth A Cimini, Thouis R Jones, Melina Claussnitzer, Peder Madsen, Hideto Takahashi, Ditte Demontis, Søren ThirupSimon Glerup

Research output: Working paper/Preprint › Preprint

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.

Original language	English
Publisher	Research Square
DOIs	https://doi.org/10.1101/2025.02.16.638491 https://doi.org/10.21203/rs.3.rs-5928514/v1
Publication status	Published - 2 Jun 2025

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Kaas, M., Chofflet, N., Bicer, D., Skeldal, S., Duan, J., Feller, B., Vilstrup, J., Groth, R., Sivagurunathan, S., Dashti, H., Pedersen, J. S., Werge, T., Børglum, A. D., Cimini, B. A., Jones, T. R., Claussnitzer, M., Madsen, P., Takahashi, H., Demontis, D., ... Glerup, S. (2025). Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation. Research Square. https://doi.org/10.1101/2025.02.16.638491, https://doi.org/10.21203/rs.3.rs-5928514/v1

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

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.",

author = "Mathias Kaas and Nicolas Chofflet and Deniz Bicer and Sune Skeldal and Jinjie Duan and Benjamin Feller and Joachim Vilstrup and Rosa Groth and Suganya Sivagurunathan and Hesam Dashti and Pedersen, \{Jan Skov\} and Thomas Werge and B{\o}rglum, \{Anders D\} and Cimini, \{Beth A\} and Jones, \{Thouis R\} and Melina Claussnitzer and Peder Madsen and Hideto Takahashi and Ditte Demontis and S{\o}ren Thirup and Simon Glerup",

year = "2025",

month = jun,

day = "2",

doi = "10.1101/2025.02.16.638491",

language = "English",

publisher = " Research Square",

type = "WorkingPaper",

institution = " Research Square",

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Kaas, M, Chofflet, N, Bicer, D , Skeldal, S , Duan, J, Feller, B, Vilstrup, J, Groth, R, Sivagurunathan, S, Dashti, H, Pedersen, JS, Werge, T, Børglum, AD, Cimini, BA, Jones, TR, Claussnitzer, M, Madsen, P, Takahashi, H, Demontis, D , Thirup, S & Glerup, S 2025 'Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation' Research Square. https://doi.org/10.1101/2025.02.16.638491, https://doi.org/10.21203/rs.3.rs-5928514/v1

TY - UNPB

T1 - Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation

AU - Kaas, Mathias

AU - Chofflet, Nicolas

AU - Bicer, Deniz

AU - Skeldal, Sune

AU - Duan, Jinjie

AU - Feller, Benjamin

AU - Vilstrup, Joachim

AU - Groth, Rosa

AU - Sivagurunathan, Suganya

AU - Dashti, Hesam

AU - Pedersen, Jan Skov

AU - Werge, Thomas

AU - Børglum, Anders D

AU - Cimini, Beth A

AU - Jones, Thouis R

AU - Claussnitzer, Melina

AU - Madsen, Peder

AU - Takahashi, Hideto

AU - Demontis, Ditte

AU - Thirup, Søren

AU - Glerup, Simon

PY - 2025/6/2

Y1 - 2025/6/2

N2 - 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.

AB - 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.

U2 - 10.1101/2025.02.16.638491

DO - 10.1101/2025.02.16.638491

M3 - Preprint

C2 - 40027832

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

PB - Research Square

ER -

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

Abstract

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