A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia.
Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene. A case-control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P = 0.05, Mann-Whitney test), with longer alleles overly represented in patients. An in-vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)(n) repeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P = 0.01, Spearman's Rank test). These results illustrate a genotype-phenotype correlation in schizophrenia and suggest that the longer (GT)(n) stretch may act as a risk-conferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Masanari
M
Itokawa
Kazuo
K
Yamada
Kiyoshi
K
Yoshitsugu
Tomoko
T
Toyota
Toshiro
T
Suga
Hisako
H
Ohba
Akiko
A
Watanabe
Eiji
E
Hattori
Hiromitsu
H
Shimizu
Tetsuo
T
Kumakura
Mitsuru
M
Ebihara
Joanne M
JM
Meerabux
Michio
M
Toru
Takeo
T
Yoshikawa
D000328:Adult; D000368:Aged; D001483:Base Sequence; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D016896:Treatment Outcome
D017931:DNA Primers; D018076:DNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate