Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth.
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.
Budel
Stéphane
S
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Padukkavidana
Thihan
T
Liu
Betty P
BP
Feng
Zeny
Z
Hu
Fenghua
F
Johnson
Sam
S
Lauren
Juha
J
Park
James H
JH
McGee
Aaron W
AW
Liao
Ji
J
Stillman
Althea
A
Kim
Ji-Eun
JE
Yang
Bao-Zhu
BZ
Sodi
Stefano
S
Gelernter
Joel
J
Zhao
Hongyu
H
Hisama
Fuki
F
Arnsten
Amy F T
AF
Strittmatter
Stephen M
SM
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D019556:COS Cells; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D003062:Codon / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D006131:Growth Inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics; D000070816:Nogo Receptor 1; D009924:Organ Culture Techniques; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
D003062:Codon; D058851:GPI-Linked Proteins; D006131:Growth Inhibitors; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface