Neurexin 1 (NRXN1) Deletions in Schizophrenia
Open accessAbstract
Over the last 2 years, several reports have suggested that submicroscopic chromosomal deletions that disrupt the gene neurexin 1 (NRXN1) increase the risk of developing schizophrenia. In this article, we will review the evidence for this association. NRXN1 encodes NRXN1, a synaptic neuronal adhesion molecule. NRXNs are found presynaptically and are believed to interact with postsynaptic neuroligins (NLGNs) in excitatory and inhibitory synapses in the brain. The structure and possible function of NRXNs and NLGNs have recently been comprehensively reviewed.1 Vertebrate NRXNs and NLGNs are the only adhesion molecules for which a specifically synaptic function has been demonstrated.1 Current evidence suggests that NRXNs and NLGNs act transsynaptically to mediate essential signaling between presynaptic and postsynaptic specializations. Evidence from cell culture experiments and the study of mouse knockouts suggest that these molecules are required for synapse function but not for synapse formation, that they influence transsynaptic activation of synaptic transmission; and that their dysfunction impairs the properties of synapses and disrupts neural networks without completely abolishing synaptic transmission. NRXNs and NLGNs probably function by binding to each other and by interacting with intracellular proteins (most notably those with PDZ domain), but the precise mechanisms involved remain unknown.1 Whatever the mechanism and their relationship to synaptic function, it is clear that mice lacking NRXNs or NLGNs show marked deficits in synaptic transmission.1 There are 5 NLGN genes and 3 NRXN genes in humans (NRXN1 [2p16.3], NRXN2 [11q13], NRXN3 [14q31]). The 3 NRXN genes each encode an α protein and a β protein from independent promoters. NRXNs have a striking molecular diversity: the messenger RNA can be processed by alternative splicing, giving potentially thousands of distinct protein isoforms.2 There is strong evidence for an involvement of NLGNs and NRXN1 in autism (reviewed by Kumar and Christian3). Several studies reported an increased rate of deletions or other genetic variants in NRXN1 in subjects suffering with autism.4–11 Additionally, deletions in this gene have been implicated in mental retardation and developmental delay.12,13 A number of studies have reported NRXN1 deletions in cases with schizophrenia, which we will review in more detail. The first suggestion that NRXN1 deletions might confer risk of schizophrenia came from a study by Kirov et al.14 They used array comparative genome hybridization (array-CGH) to screen the genomes of 93 cases of schizophrenia recruited in Bulgaria with approximately 35 000 probes for chromosomal copy number variants (CNVs) at a resolution of about 80 000 bp. They identified a deletion of NRXN1 in a female case, which was also present in her affected brother. The deletion spanned the promoter and the first exon of the gene. Neither sibling had signs of premorbid cognitive problems or dysmorphic features. Given that deletions of NRXN1 were not seen in 372 controls, and at that time there were reports of NRXN1 deletions and point mutations in autism4,5 and one deletion in a subject with mental retardation,12 the authors hypothesized that deletions in this gene might confer risk to schizophrenia as well as to other neurodevelopmental disorders. Intriguingly, these authors also found a de novo duplication of 1.4Mb of chromosome 15 that involved, among other genes, amyloid beta A4 precursor protein-binding (APBA2) gene encoding a protein known as Mint2. Mint2 is a neuronal adaptor protein that binds directly to NRXNs in a PDZ domain–mediated interaction. Shortly after this initial report, Walsh et al,15 also using array-CGH, reported identical twins with early-onset schizophrenia who shared a 115-kb deletion in the gene (disrupting exons in the 3′ end) among a total of 233 schizophrenia cases and 268 controls. Array technology has progressed tremendously since these small early reports, and it is now possible routinely to detect CNVs using microarrays with up to 2 million probes covering the whole genome. Several groups have found deletions of NRXN1 in patients with schizophrenia using the new technologies. Rujescu et al16 examined NRXN1 for CNVs in 2977 schizophrenia patients and 33 746 control subjects from 7 European countries (Iceland, Finland, Norway, Germany, the Netherlands, Italy, and the UK). Sixty-one NRXN1 deletions, including a de novo deletion, and 5 duplications were detected. Of these, 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared with 49 deletions and 3 duplications (0.15%) among the >10-fold larger control sample (P = .13, odds ratio [OR] = 1.73; 95% confidence interval [CI] = 0.81–3.50). There was no common breakpoint, and the CNVs varied in size from 18 to 420 kb. Because the penetrance of NRXN1 CNVs is likely to vary according to the level of functional impact on the gene, these authors next restricted analysis t
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Several individual CNV loci have been strongly implicated as risk factors for schizophrenia.
“several individual CNV loci have been strongly implicated as risk factors for schizophrenia with high degrees of statistical confidence. These include deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, 22q11.2 and duplications at VIPR2, 16p11.2, 16p13.1 and 15q11-q13.2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [11]
Deletions of NRXN1 point to the importance of as yet unspecified abnormalities of synaptic function in the disorder.
“Important exceptions are deletions of NRXN1, encoding the presynaptic neuronal cell adhesion molecule neurexin 1,11, 15 pointing to the importance of as yet unspecified abnormalities of synaptic function in the disorder.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [11]
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- Authors
- Kirov, G., Rujescu, D., Ingason, A., Collier, D. A., O'Donovan, M. C., & Owen, M. J.
- Affiliations
- Cardiff University (GB)
- Ludwig-Maximilians-Universität München (DE)
- deCODE Genetics (Iceland) (IS)
- King's College London (GB)
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-08-12
- Volume
- 35
- Issue
- 5
- Pages
- 851-854
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC2728827
- OpenAlex
- W2127960585
- Cited by
- 235
- References
- 23
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 10 · 2016: 9 · 2015: 21 · 2014: 26 · 2013: 33 · 2012: 23
- FWCI
- 16.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Schizophrenia Bulletin (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- NRXN1
- MeSH terms
- Animals, Autistic Disorder, Chromosome Deletion, Diseases in Twins, Genotype, Humans, Schizophrenia, Schizophrenic Psychology, Oligonucleotide Array Sequence Analysis, Gene Duplication
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