Genetic Variants of Nogo-66 Receptor with Possible Association to Schizophrenia Block Myelin Inhibition of Axon Growth
Open accessAbstract
In schizophrenia, genetic predisposition has been linked to chromosome 22q11 and myelin-specific genes are misexpressed in schizophrenia. Nogo-66 receptor 1 (NGR or RTN4R) has been considered to be a 22q11 candidate gene for schizophrenia susceptibility because it encodes an axonal protein that mediates myelin inhibition of axonal sprouting. Confirming previous studies, we found that variation at the NGR locus is associated with schizophrenia in a Caucasian case-control analysis, and this association is not attributed to population stratification. Within a limited set of schizophrenia-derived DNA samples, we identified several rare NGR nonconservative coding sequence variants. Neuronal cultures demonstrate that four different schizophrenia-derived NgR1 variants fail to transduce myelin signals into axon inhibition, and function as dominant negatives to disrupt endogenous NgR1. This provides the first evidence that certain disease-derived human NgR1 variants are dysfunctional proteins in vitro. Mice lacking NgR1 protein exhibit reduced working memory function, consistent with a potential endophenotype of schizophrenia. For a restricted subset of individuals diagnosed with schizophrenia, the expression of dysfunctional NGR variants may contribute to increased disease risk.
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PAK7 and GABRD have been associated with schizophrenia.
“PAK7 and GABRD which have been associated with schizophrenia49–52.”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [50]
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References 80 · Cited by 107
- Authors
- Budel, S., Padukkavidana, T., Liu, B. P., Feng, Z., Hu, F., Johnson, S., Lauren, J., Park, J. H., McGee, A. W., Liao, J., Stillman, A., Kim, J.-E., Yang, B.-Z., Sodi, S., Gelernter, J., Zhao, H., Hisama, F., Arnsten, A. F. T., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- University of Guelph (CA)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-03
- Volume
- 28
- Issue
- 49
- Pages
- 13161-13172
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2892845
- OpenAlex
- W2081528639
- Cited by
- 107
- References
- 80
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 12 · 2018: 7 · 2017: 8 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 13 · 2012: 12
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- Dr. Ralph and Marian Falk Medical Research Trust
- National Institutes of Health
- National Institute of Mental Health (U01MH046276, U01MH046318, U01MH046289)
- National Institute of Neurological Disorders and Stroke (R01NS042304, R01NS039962, R37NS033020, R01NS056485)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- Nogo-66 receptor, nerve growth factor receptor, schizophrenia, genetic association, chromosome 22q11, myelin, axon growth inhibition, dominant-negative mutant, working memory, endophenotypes
- MeSH terms
- Nogo Receptor 1, Animals, Brain, Chlorocebus aethiops, Chick Embryo, Chromosome Mapping, Codon, Female, Growth Inhibitors, Humans, Male, Mutation, Myelin Proteins, Nerve Fibers, Myelinated, Neuronal Plasticity, Organ Culture Techniques, Receptors, Cell Surface, Schizophrenia, Mice, Knockout, COS Cells, Genetic Predisposition to Disease, Growth Cones, Mice, Rats, Neurogenesis, GPI-Linked Proteins
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