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Neurexins in autism and schizophrenia—a review of patient mutations, mouse models and potential future directions

Molecular Psychiatry volume 26, pages 747–760 (2021)Cite this article

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Abstract

Mutations in the family of neurexins (NRXN1, NRXN2 and NRXN3) have been repeatedly identified in patients with autism spectrum disorder (ASD) and schizophrenia (SCZ). However, it remains unclear how these DNA variants affect neurexin functions and thereby predispose to these neurodevelopmental disorders. Understanding both the wild-type and pathologic roles of these genes in the brain could help unveil biological mechanisms underlying mental disorders. In this regard, numerous studies have focused on generating relevant loss-of-function (LOF) mammalian models. Although this has increased our knowledge about their normal functions, the potential pathologic role(s) of these human variants remains elusive. Indeed, after reviewing the literature, it seems apparent that a traditional LOF-genetic approach based on complete LOF might not be sufficient to unveil the role of these human mutations. First, these genes present a very complex transcriptome and total-LOF of all isoforms may not be the cause of toxicity in patients, particularly given evidence that causative variants act through haploinsufficiency. Moreover, human DNA variants may not all lead to LOF but potentially to intricate transcriptome changes that could also include the generation of aberrant isoforms acting as a gain-of-function (GOF). Furthermore, their transcriptomic complexity most likely renders them prone to genetic compensation when one tries to manipulate them using traditional site-directed mutagenesis approaches, and this could act differently from model to model leading to heterogeneous and conflicting phenotypes. This review compiles the relevant literature on variants identified in human studies and on the mouse models currently deployed, and offers suggestions for future research.

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Fig. 1: Domain organisation of α-neurexins and β-neurexins.
Fig. 2: Map of NRXN1 mutations.
Fig. 3: Map of NRXN2 and NRXN3 mutations.
Fig. 4: NRXN mutations generated in mouse models.

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Acknowledgements

This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC) Project Grant no. 1165850 to BM and JG, The Rebecca Cooper Medical Research Project Grant no. PG2019405 to JG. JG was also supported by a NHMRC Emerging Leader Fellowship no. 1174145.

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  1. These authors contributed equally: Bryan Mowry, Jean Giacomotto

Authors and Affiliations

  1. Queensland Brain Institute, University of Queensland, St Lucia, QLD, Australia

    Alisha Tromp, Bryan Mowry & Jean Giacomotto

  2. Queensland Centre for Mental Health Research, Brisbane, QLD, Australia

    Bryan Mowry & Jean Giacomotto

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  1. Alisha Tromp
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  2. Bryan Mowry
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  3. Jean Giacomotto
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Correspondence to Bryan Mowry or Jean Giacomotto.

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Tromp, A., Mowry, B. & Giacomotto, J. Neurexins in autism and schizophrenia—a review of patient mutations, mouse models and potential future directions. Mol Psychiatry 26, 747–760 (2021). https://doi.org/10.1038/s41380-020-00944-8

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