NRXN1 – NRXN1-related Schizophrenia

NRXN1 encodes neurexin-1, a presynaptic cell adhesion molecule essential for synapse formation and neurotransmission. Heterozygous loss-of-function variants in NRXN1 cluster in the 2p16.3 region and disrupt the α-isoform predominantly expressed in cortical and hippocampal neurons. NRXN1 interacts with postsynaptic partners such as neuroligin-1 and LRRTM2 to coordinate synaptic differentiation.

Initial genome-wide screens identified recurrent exon-disrupting deletions in NRXN1 in schizophrenia patients (0.24% of cases vs. 0.015% of controls) (PMID:18940311). Subsequent large-scale CNV analyses across 6,882 cases and 6,316 controls confirmed a significant association of exonic NRXN1 deletions with schizophrenia (P = 4.1×10⁻⁴) (PMID:24311552). A Japanese cohort screen in 575 patients and 564 controls replicated enrichment of heterozygous NRXN1 deletions in cases (PMID:19880096).

Familial studies demonstrate segregation of NRXN1 deletions with schizophrenia in 11 multiplex families, with incomplete penetrance among carriers (PMID:24680031). The deletion is inherited from unaffected parents in some pedigrees, highlighting variable expressivity and reduced penetrance.

The NRXN1 variant spectrum includes heterozygous multi-exon deletions, single-exon intragenic rearrangements, truncating point mutations, and rare missense alleles. A representative truncating allele, c.601G>T (p.Glu201Ter), abolishes the LNS2 domain required for ligand binding and synaptic adhesion.

Functional assays in neuron–glia co-cultures show that NRXN1 truncating mutations fail to induce presynaptic differentiation and impair binding to LRRTM2 and neuroligin-2 (PMID:21424692). Activity-dependent alternative splicing of NRXN1 is regulated by SAM68, and disruption of this mechanism alters synaptic isoform balance (PMID:22196734). Human ESC-derived neurons with heterozygous NRXN1 deletions exhibit selective defects in neurotransmitter release without affecting synapse number (PMID:26279266).

Together, genetic and experimental data support a haploinsufficiency mechanism for NRXN1 in schizophrenia. While deletions confer substantial risk, incomplete penetrance mandates careful interpretation in genetic counseling. Key take-home: NRXN1 heterozygous exonic deletions are a strong, clinically actionable risk factor for schizophrenia, warranting CNV screening in diagnostic workflows.

References

• American Journal of Human Genetics • 2008 • Recurrent CNVs disrupt three candidate genes in schizophrenia patients. PMID:18940311
• The British Journal of Psychiatry • 2014 • Analysis of copy number variations at 15 schizophrenia-associated loci. PMID:24311552
• Biological Psychiatry • 2010 • Copy number variation in schizophrenia in the Japanese population. PMID:19880096
• Schizophrenia Research • 2014 • Incomplete penetrance of NRXN1 deletions in families with schizophrenia. PMID:24680031
• Human Genetics • 2011 • Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. PMID:21424692
• Cell • 2011 • SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. PMID:22196734
• Cell Stem Cell • 2015 • Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1. PMID:26279266

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