A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility

H. Kimura, Y. Fujita, T. Kawabata, K. Ishizuka, C. Wang, Y. Iwayama, Yuko Okahisa, I. Kushima, M. Morikawa, Y. Uno, T. Okada, M. Ikeda, T. Inada, A. Branko, D. Mori, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P=0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.

Original languageEnglish
Pages (from-to)e1214
JournalTranslational Psychiatry
Volume7
Issue number8
DOIs
Publication statusPublished - Aug 22 2017
Externally publishedYes

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Growth Cones
Schizophrenia
Mutation
rho-Associated Kinases
Missense Mutation
Nogo Receptor 1
Gene Frequency
Mental Disorders
Regeneration
Exons
Nucleotides
Central Nervous System
Chromosomes
Autism Spectrum Disorder
Research

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility. / Kimura, H.; Fujita, Y.; Kawabata, T.; Ishizuka, K.; Wang, C.; Iwayama, Y.; Okahisa, Yuko; Kushima, I.; Morikawa, M.; Uno, Y.; Okada, T.; Ikeda, M.; Inada, T.; Branko, A.; Mori, D.; Yoshikawa, T.; Iwata, N.; Nakamura, H.; Yamashita, T.; Ozaki, N.

In: Translational Psychiatry, Vol. 7, No. 8, 22.08.2017, p. e1214.

Research output: Contribution to journalArticle

Kimura, H, Fujita, Y, Kawabata, T, Ishizuka, K, Wang, C, Iwayama, Y, Okahisa, Y, Kushima, I, Morikawa, M, Uno, Y, Okada, T, Ikeda, M, Inada, T, Branko, A, Mori, D, Yoshikawa, T, Iwata, N, Nakamura, H, Yamashita, T & Ozaki, N 2017, 'A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility', Translational Psychiatry, vol. 7, no. 8, pp. e1214. https://doi.org/10.1038/tp.2017.170
Kimura, H. ; Fujita, Y. ; Kawabata, T. ; Ishizuka, K. ; Wang, C. ; Iwayama, Y. ; Okahisa, Yuko ; Kushima, I. ; Morikawa, M. ; Uno, Y. ; Okada, T. ; Ikeda, M. ; Inada, T. ; Branko, A. ; Mori, D. ; Yoshikawa, T. ; Iwata, N. ; Nakamura, H. ; Yamashita, T. ; Ozaki, N. / A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility. In: Translational Psychiatry. 2017 ; Vol. 7, No. 8. pp. e1214.
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AU - Inada, T.

AU - Branko, A.

AU - Mori, D.

AU - Yoshikawa, T.

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