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The Journal of Neuroscience, December 3, 2008, 28(49):13161-13172; doi:10.1523/JNEUROSCI.3828-08.2008

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Neurobiology of Disease
Genetic Variants of Nogo-66 Receptor with Possible Association to Schizophrenia Block Myelin Inhibition of Axon Growth

Stéphane Budel,¹ Thihan Padukkavidana,¹ Betty P. Liu,¹ Zeny Feng,^2,3,6 Fenghua Hu,¹ Sam Johnson,⁴ Juha Lauren,¹ James H. Park,¹ Aaron W. McGee,¹ Ji Liao,¹ Althea Stillman,¹ Ji-Eun Kim,¹ Bao-Zhu Yang,⁵ Stefano Sodi,¹ Joel Gelernter,⁵ Hongyu Zhao,^2,3 Fuki Hisama,¹ Amy F. T. Arnsten,⁴ and Stephen M. Strittmatter^1,4

¹Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of ²Epidemiology and Public Health, ³Genetics, ⁴Neurobiology, and ⁵Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06536, and ⁶Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada N1G 2W1

Correspondence should be addressed to Stephen M. Strittmatter, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, P.O. Box 9812, New Haven, CT 06536-0812. Email: stephen.strittmatter{at}yale.edu

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.

Key words: schizophrenia; myelin; genetic linkage; axonal growth; Nogo; plasticity

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Received Aug. 12, 2008; revised Oct. 6, 2008; accepted Oct. 22, 2008.

Correspondence should be addressed to Stephen M. Strittmatter, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, P.O. Box 9812, New Haven, CT 06536-0812. Email: stephen.strittmatter{at}yale.edu

Related articles in J. Neurosci.:

Converging Evidence for the Nogo-66 Receptor Gene in Schizophrenia

Aristotle N. Voineskos
J. Neurosci. 2009 29: 5045-5047. [Full Text]  

This article has been cited by other articles:

				A. N. Voineskos Converging Evidence for the Nogo-66 Receptor Gene in Schizophrenia J. Neurosci., April 22, 2009; 29(16): 5045 - 5047. [Full Text] [PDF]

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