Disruption of neurexin 1 associated with autism spectrum disorder
Open accessAbstract
Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
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The neurexin-1 (nrxn1) gene has been linked directly to ASD and SCZ.
“Of these, the neurexin-1 (nrxn1) gene has been linked directly to ASD and SCZ (Kim et al. 2008; Rujescu et al. 2009, Glessner et al. 2009; Ching et al. 2010; Gauthier et al. 2011).”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Kim et al. 2008
The paper’s opening section (p. 1) implicates NRXN1 in autism spectrum disorder, supporting the ASD part of the claim. The copy does not link NRXN1 to schizophrenia (SCZ); a search for “schizophrenia” found no such passage. The other citations may support that part, but this verdict concerns Kim et al. only. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMutations in some of these genes such as genes encoding cadherins and neurexin-neuroligins in human, which were differentially methylated following exposure to adverse maternal environment in mice, have been associated with ASD (179-182).
“mutations in some of these genes such as genes encoding cadherins and neurexin–neuroligins in human, which were differentially methylated following exposure to adverse maternal environment in mice, have been associated with ASD (179–182).”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [180]
Shank2, SAPAP2, Neurexin-1, Neuroligin-3 and Neuroligin-4 have been implicated in human ASDs.
“In addition to Shank39, it is worth noting that Shank26,8, SAPAP26, Neurexin-126, Neuroligin-3 and −427 have all been implicated in human ASDs.”
From Shank3 mutant mice display autistic-like behaviours and striatal dysfunction (2011) · cites this paper as [26]
NRXN1 has previously been linked to ASD.
“NRXN1, which has been previously associated with ASD [42]”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [42]
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“To investigate the sensitivity to psychostimulant drugs, we assessed the hyperactivity evoked by amphetamine (that stimulates the release of dopamine, noradrenaline and serotonin), that is also used for the treatment of ADHD (Biederman and Faraone 2005; Feldman and Reiff 2014) but exacerbates positive symptoms of SCZ…”
Influential
- Authors
- Kim, H.-G., Kishikawa, S., Higgins, A. W., Seong, I.-S., Donovan, D. J., Shen, Y., Lally, E., Weiss, L. A., Najm, J., Kutsche, K., Descartes, M., Holt, L., Braddock, S., Troxell, R., Kaplan, L., Volkmar, F., Klin, A., Tsatsanis, K., Harris, D. J., Noens, I., Pauls, D. L., Daly, M. J., MacDonald, M. E., Morton, C. C., Quade, B. J., & Gusella, J. F.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Alabama at Birmingham (US)
- University of Virginia Health System (US)
- University of Missouri (US)
- Yale University (US)
- Boston Children's Hospital (US)
- Leiden University (NL)
- Corresponding author
- Gusella, James F.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 82
- Issue
- 1
- Pages
- 199-207
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2253961
- OpenAlex
- W1976358763
- Cited by
- 578
- References
- 43
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 20 · 2023: 7 · 2022: 15 · 2021: 16 · 2020: 21 · 2019: 23 · 2018: 24 · 2017: 25 · 2016: 29 · 2015: 26 · 2014: 42 · 2013: 51 · 2012: 59
- FWCI
- 34.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute of Mental Health (NS16648, MH 64547, R01MH064547)
- National Institute of General Medical Sciences (P01GM061354)
- National Institute of Neurological Disorders and Stroke (R01NS016648)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19HD035482, P01HD003008)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- NRXN1, autism spectrum disorder, translocation, penetrance, genetic susceptibility, rare variants, missense mutations, EGF-like domain, 5' untranslated region, neurodevelopmental disorders
- MeSH terms
- Autistic Disorder, Chromosome Aberrations, Chromosomes, Human, Pair 2, Glycoproteins, Humans, Neuropeptides, Sequence Analysis, DNA, Protein Structure, Tertiary, Genetic Predisposition to Disease, Mutation, Missense
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