Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia.
Fyn, a Src-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, Fyn participates in brain development, synaptic transmission through the phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that Fyn is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether Fyn abnormalities are present in patients with schizophrenia, we analyzed Fyn expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of Fyn protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of fyn were altered in the patients and their relatives; specifically, the ratio of fynDelta7, in which exon 7 is absent, was elevated. An expression study in HEK293T cells revealed that FynDelta7 had a dominant-negative effect on the phosphorylation of Fyn's substrate. These results suggest novel deficits in Fyn function, manifested as the downregulation of Fyn protein or the altered transcription of the fyn gene, in patients with schizophrenia.
Hattori
Kotaro
K
KOKORO Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Suita 565-0871, Japan.
Fukuzako
Hiroshi
H
Hashiguchi
Tomo
T
Hamada
Shun
S
Murata
Yoji
Y
Isosaka
Tomoko
T
Yuasa
Shigeki
S
Yagi
Takeshi
T
D000328:Adult; D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D015536:Down-Regulation / Q000235:genetics; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism; D005190:Family; D005260:Female; D015870:Gene Expression; D006801:Humans; D047668:Inteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000097:blood / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D009363:Neoplasm Proteins; D012333:RNA, Messenger; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D005092:Exonucleases; C413215:exoN protein, human