Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility

Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu TakakiShinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-d-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

Original languageEnglish
Article number61
JournalTranslational psychiatry
Volume8
Issue number1
DOIs
Publication statusPublished - 01-12-2018

Fingerprint

Glutamate Receptors
Schizophrenia
Mutation
Frameshift Mutation
Pedigree
Computer Simulation
Introns
Genes
Glutamic Acid
aspartic acid receptor
Autism Spectrum Disorder

All Science Journal Classification (ASJC) codes

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

Cite this

Yu, Yanjie ; Lin, Yingni ; Takasaki, Yuto ; Wang, Chenyao ; Kimura, Hiroki ; Xing, Jingrui ; Ishizuka, Kanako ; Toyama, Miho ; Kushima, Itaru ; Mori, Daisuke ; Arioka, Yuko ; Uno, Yota ; Shiino, Tomoko ; Nakamura, Yukako ; Okada, Takashi ; Morikawa, Mako ; Ikeda, Masashi ; Iwata, Nakao ; Okahisa, Yuko ; Takaki, Manabu ; Sakamoto, Shinji ; Someya, Toshiyuki ; Egawa, Jun ; Usami, Masahide ; Kodaira, Masaki ; Yoshimi, Akira ; Oya-Ito, Tomoko ; Aleksic, Branko ; Ohno, Kinji ; Ozaki, Norio. / Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. In: Translational psychiatry. 2018 ; Vol. 8, No. 1.
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title = "Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility",
abstract = "In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-d-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.",
author = "Yanjie Yu and Yingni Lin and Yuto Takasaki and Chenyao Wang and Hiroki Kimura and Jingrui Xing and Kanako Ishizuka and Miho Toyama and Itaru Kushima and Daisuke Mori and Yuko Arioka and Yota Uno and Tomoko Shiino and Yukako Nakamura and Takashi Okada and Mako Morikawa and Masashi Ikeda and Nakao Iwata and Yuko Okahisa and Manabu Takaki and Shinji Sakamoto and Toshiyuki Someya and Jun Egawa and Masahide Usami and Masaki Kodaira and Akira Yoshimi and Tomoko Oya-Ito and Branko Aleksic and Kinji Ohno and Norio Ozaki",
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Yu, Y, Lin, Y, Takasaki, Y, Wang, C, Kimura, H, Xing, J, Ishizuka, K, Toyama, M, Kushima, I, Mori, D, Arioka, Y, Uno, Y, Shiino, T, Nakamura, Y, Okada, T, Morikawa, M, Ikeda, M, Iwata, N, Okahisa, Y, Takaki, M, Sakamoto, S, Someya, T, Egawa, J, Usami, M, Kodaira, M, Yoshimi, A, Oya-Ito, T, Aleksic, B, Ohno, K & Ozaki, N 2018, 'Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility', Translational psychiatry, vol. 8, no. 1, 61. https://doi.org/10.1038/s41398-017-0061-y

Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. / Yu, Yanjie; Lin, Yingni; Takasaki, Yuto; Wang, Chenyao; Kimura, Hiroki; Xing, Jingrui; Ishizuka, Kanako; Toyama, Miho; Kushima, Itaru; Mori, Daisuke; Arioka, Yuko; Uno, Yota; Shiino, Tomoko; Nakamura, Yukako; Okada, Takashi; Morikawa, Mako; Ikeda, Masashi; Iwata, Nakao; Okahisa, Yuko; Takaki, Manabu; Sakamoto, Shinji; Someya, Toshiyuki; Egawa, Jun; Usami, Masahide; Kodaira, Masaki; Yoshimi, Akira; Oya-Ito, Tomoko; Aleksic, Branko; Ohno, Kinji; Ozaki, Norio.

In: Translational psychiatry, Vol. 8, No. 1, 61, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility

AU - Yu, Yanjie

AU - Lin, Yingni

AU - Takasaki, Yuto

AU - Wang, Chenyao

AU - Kimura, Hiroki

AU - Xing, Jingrui

AU - Ishizuka, Kanako

AU - Toyama, Miho

AU - Kushima, Itaru

AU - Mori, Daisuke

AU - Arioka, Yuko

AU - Uno, Yota

AU - Shiino, Tomoko

AU - Nakamura, Yukako

AU - Okada, Takashi

AU - Morikawa, Mako

AU - Ikeda, Masashi

AU - Iwata, Nakao

AU - Okahisa, Yuko

AU - Takaki, Manabu

AU - Sakamoto, Shinji

AU - Someya, Toshiyuki

AU - Egawa, Jun

AU - Usami, Masahide

AU - Kodaira, Masaki

AU - Yoshimi, Akira

AU - Oya-Ito, Tomoko

AU - Aleksic, Branko

AU - Ohno, Kinji

AU - Ozaki, Norio

PY - 2018/12/1

Y1 - 2018/12/1

N2 - In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-d-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

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