臨床検査55巻9号

2011年09月発行

今月の主題 RNAの解析 各論 〈病態疾患と動態解析〉

スプライシング異常から解析する統合失調症

著者： 眞部孝幸¹ 前田明¹

所属機関： ¹藤田保健衛生大学総合医科学研究所遺伝子発現機構学研究部門

ページ範囲：P.893 - P.899

神経細胞やグリア細胞などの神経系細胞の遺伝子発現調節に，選択的スプライシングが重要な役割を演じている．それゆえに，この調節機構の破綻は重篤な発達障害や疾患発現の引き金となる．近年多くの神経変性疾患や精神疾患において種々の遺伝子のスプライシング異常が報告されている．本稿では，最近急速に報告され始めた統合失調症における選択的スプライシングの異常に焦点を当て，最新の情報を紹介しつつ，異常スプライシングを標的とした診断・治療への可能性について解説する．

参考文献

1) Cartegni L, Chew SL, Krainer AR : Listening to silence and understanding nonsense : exonic mutations that affect splicing. Nat Rev Genet　3：285-298，2002

2) Morikawa T, Manabe T : Aberrant regulation of alternative pre-mRNA splicing in schizophrenia. Neurochem Int　57：691-704，2010

3) Licatalosi DD, Darnell RB : Splicing regulation in neurologic disease. Neuron　52：93-101，2006

4) Li Q, Lee JA, Black DL : Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci　8：819-831，2007

5) Ross CA, Margolis RL, Reading SA, et al : Neurobiology of schizophrenia. Neuron　52：139-153，2006

6) Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, et al : Neurodevelopmental mechanisms of schizophrenia : understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci　32：485-495，2009

7) Zhang Y, Bertolino A, Fazio L, et al : Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A　104：20552-20557，2007

-receptor pre-mRNA in chronic schizophrenia. J Neurosci　16：7902-7909，1996

subunit with different electrophysiological properties : differential expression and genotypical correlations in schizophrenia. Mol Psychiatry　11：1092-1105，2006

subunit gene : relationships between novel isoforms and psychotic disorders. PLoS One　4：e6977，2009

11) Huntsman MM, Tran BV, Potkin SG, et al : Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci U S A　95：15066-15071，1998

12) Sartorius LJ, Weinberger DR, Hyde TM, et al : Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP. Neuropsychopharmacology　33：2626-2634，2008

13) Clinton SM, Haroutunian V, Davis KL, et al : Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am J Psychiatry　160：1100-1109，2003

14) Le Corre S, Harper CG, Lopez P, et al : Increased levels of expression of an NMDARI splice variant in the superior temporal gyrus in schizophrenia. Neuroreport　11：983-986，2000

15) Mukai J, Liu H, Burt RA, et al : Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet　36：725-731，2004

16) Ding L, Hegde AN : Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients. Biol Psychiatry　65：541-545，2009

17) Nakata K, Lipska BK, Hyde TM, et al : DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci U S A　106：15873-15878，2009

18) Law AJ, Lipska BK, Weickert CS, et al : Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′SNPs associated with the disease. Proc Natl Acad Sci USA　103：6747-6752，2006

19) Hashimoto R, Straub RE, Weickert CS, et al : Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol Psychiatry　9：299-307，2004

20) Law AJ, Kleinman JE, Weinberger DR, et al : Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet　16：129-141，2007

21) Poltorak M, Khoja I, Hemperly JJ, et al : Disturbances in cell recognition molecules (N-CAM and L1antigen) in the CSF of patients with schizophrenia. Exp Neurol　131：266-272，1995

22) Gibbons AS, Thomas EA, Dean B : Regional and duration of illness differences in the alteration of NCAM-180 mRNA expression within the cortex of subjects with schizophrenia. Schizophr Res　112：65-71，2009

23) Vawter MP : Dysregulation of the neural cell adhesion molecule and neuropsychiatric disorders. Eur J Pharmacol　405：385-395，2000

24) Mexal S, Berger R, Pearce L, et al : Regulation of a novel αN-catenin splice variant in schizophrenic smokers. Am J Med Genet B Neuropsychiatr Genet　147B：759-768，2008

25) Hattori K, Fukuzako H, Hashiguchi T, et al : Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia. Psychiatry Res　168：119-128，2009

26) Aberg K, Saetre P, Lindholm E, et al : Human QKI, a new candidate gene for schizophrenia involved in myelination. Am J Med Genet B Neuropsychiatr Genet　141B：84-90，2006

27) Aberg K, Saetre P, Jareborg N, et al : Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci U S A　103：7482-7487，2006

28) Weickert CS, Miranda-Angulo AL, Wong J, et al : Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia. Hum Mol Genet　17：2293-2309，2008

29) Smith MJ, Sharples RA, Evin G, et al : Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex. Mol Brain Res　127：128-135，2004

30) Mei L, Xiong WC : Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci　9：437-452，2008

31) Manabe T, Ohe K, Katayama T, et al : HMGA1a : sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA. Genes Cells　12：1179-1191，2007

32) Hua Y, Sahashi K, Hung G, et al : Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev　24：1634-1644，2010