Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia

Sinibaldi, Lorenzo; Luca, Alessandro De; Bellacchio, Emanuele; Conti, Emanuela; Pasini, Augusto; Paloscia, Claudio; Spalletta, Gianfranco; Caltagirone, Carlo; Pizzuti, Antonio; Dallapiccola, Bruno

doi:10.1002/humu.9292

Cited by 68 publications

(77 citation statements)

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“…Rtn4R is an attractive candidate gene, as it has been observed to play a role in the inhibition of neurite elongation (Oertle et al, 2003). Moreover, an association has been shown between Rtn4R gene mutations and the risk for developing schizophrenia (Sinibaldi et al, 2004). These findings support the hypothesis that genetically influenced abnormalities in the coordinated development of the thalamus and cortex may lead to psychotic symptoms in several neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 61%

“…An interesting candidate gene in the vicinity of D16Mit100 is the reticulon 4 receptor gene (Rtn4R), located 6.1 Mb from the peak. In humans, this gene is located at 22q11 (Sinibaldi et al, 2004), near the recent schizophrenia candidate genes encoding PRODH and COMT (Fan et al, 2003;Williams et al, 2003;Lee et al, 2005). Rtn4R is an attractive candidate gene, as it has been observed to play a role in the inhibition of neurite elongation (Oertle et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

et al. 2007

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To investigate whether there are separate or shared genetic influences on the development of the thalamus and cerebral cortex, we identified quantitative trait loci (QTLs) for relevant structural volumes in BXD recombinant inbred (RI) strains of mice. In 34 BXD RI strains and two parental strains (C57BL/ 6J and DBA/2J), we measured the volumes of the entire thalamus and cortex gray matter using point counting and Cavalieri's rule. Heritability was calculated using analysis of variance (ANOVA), and QTL analysis was carried out using WebQTL (http://www.genenetwork.org). The heritability of thalamus volume was 36%, and three suggestive QTLs for thalamus volume were identified on chromosomes 10, 11 and 16. The heritability of cortical gray matter was 43%, and four suggestive QTLs for cortex gray matter volume were identified on chromosomes 2, 8, 16 and 19. The genetic correlation between thalamus and cortex gray matter volumes was 0.64. Also, a single QTL on chromosome 16 (D16Mit100) was identified for thalamus volume, cortex gray matter volume and Morris water maze search-time preference (r ¼ 0.71). These results suggest that there are separate and shared genetic influences on the development of the thalamus and cerebral cortex.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

et al. 2007

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“…141 This gene encodes for a functional cell-surface receptor, a GPI-linked protein, which is implicated in axonal growth inhibition. 141 It maps on chromosome 22q11.2, within the velocardiofacial syndrome's locus, and mutations of the RTN4R are associated with the disorder. Besides Nogo, two other myelin proteins bind to the RTN4R: MAG and MOG, which have already been shown to be related to schizophrenia.…”

Section: Cnp 17q21mentioning

confidence: 99%

The myelin-pathogenesis puzzle in schizophrenia: a literature review

2007

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Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.

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“…Moreover, Nogo receptor 1 (RTN4R, NgR1), a putative receptor subunit for Nogo-A, is encoded by a gene located on chromosome 22q11, which is a hotspot for genetic predisposition in schizophrenia (Liu et al, 2002). Recently, several NgR1 mutations have also been identified in schizophrenic patients (Sinibaldi et al, 2004;Hsu et al, 2007;Budel et al, 2008).Schizophrenia is a severe and chronic neuropsychiatric disorder with a presumed etiology in abnormal neurodevelopment attributable to combinatorial effects of environmental and genetic risk factors (Harrison, 1997;Lewis and Levitt, 2002;Rapoport et al, 2005). Indeed, various genetic linkage and association studies have identified genomic regions that may harbor schizophrenia susceptibility genes (Harrison and Weinberger, 2005;Ross et al, 2006).…”

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confidence: 99%

Constitutive Genetic Deletion of the Growth Regulator Nogo-A Induces Schizophrenia-Related Endophenotypes

Willi¹,

Weinmann²,

Winter³

et al. 2010

J. Neurosci.

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The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders. IntroductionNogo-A is well known for its crucial role as a myelin-associated inhibitor of regenerative fiber growth and structural plasticity in the injured adult CNS (Schwab, 2004;Yiu and He, 2006). In the intact adult CNS, Nogo-A acts as a suppressor of growth and sprouting, thus stabilizing the wiring of the adult CNS (Buffo et al., 2000;Bareyre et al., 2002). Nogo-A is not only expressed in oligodendrocytes, but it is also present in subsets of neurons (Huber et al., 2002;Wang et al., 2002). Neuronal Nogo-A is especially highly expressed in the fetal and early postnatal brain and is downregulated in most anatomical structures in adulthood, except in some regions of high plasticity (e.g., hippocampus), in which neuronal Nogo-A expression remains high (Huber et al., 2002). Nogo-A might therefore assume critical control over neurodevelopmental processes as well as neural plasticity events. A recent report has emphasized Nogo's possible involvement in cortical development and neuronal maturation (Mingorance-Le Meur et al., 2007). Although controversial, human postmortem and genetic linkage studies have implicated Nogo-A and its chromosomal location in several neuropsychiatric disorders with a presumed neurodevelopmental origin, namely schizophrenia and bipolar disorder (Coon et al., 1998;Shaw et al., 1998;Novak et al., 20...

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Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia

Cited by 68 publications

References 20 publications

Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

The myelin-pathogenesis puzzle in schizophrenia: a literature review

Constitutive Genetic Deletion of the Growth Regulator Nogo-A Induces Schizophrenia-Related Endophenotypes

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