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.

• Authors: 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 Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki
• Journal: Translational psychiatry (Transl Psychiatry) Vol. 8 Issue 1 Pg. 12 (01 10 2018) ISSN: 2158-3188 [Electronic] United States
• PMID: 29317596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GRIN2C protein, human
• GRIN2D protein, human
• Receptors, N-Methyl-D-Aspartate

Topics

• Adolescent
• Adult
• Autism Spectrum Disorder (genetics)
• Case-Control Studies
• Child
• Exons
• Female
• Genetic Predisposition to Disease
• Humans
• Loss of Function Mutation
• Male
• Middle Aged
• Receptors, N-Methyl-D-Aspartate (genetics)
• Schizophrenia (genetics)
• Young Adult