Exomic sequencing of the ionotropic glutamate receptor N-methyl-D-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia.
BACKGROUND
Growing evidence suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia.


METHODS
We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia.


RESULTS
We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p=0.011, Fisher's exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging.


CONCLUSIONS
Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients.
Shen
Yu-Chih
YC
Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan; Department of Psychiatry, Tzu-Chi Medical Center and University, Hualien, Taiwan.
Liao
Ding-Lieh
DL
Chen
Jen-Yeu
JY
Wang
Ying-Chieh
YC
Lai
I-Ching
IC
Liou
Ying-Jay
YJ
Chen
Yu-Jun
YJ
Luu
Sy-Ueng
SU
Chen
Chia-Hsiang
CH
D000328:Adult; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018091:Receptors, AMPA / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D013624:Taiwan
D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3