Evidence for X-chromosomal schizophrenia associated with microRNA alterations.
Evidence for X-chromosomal schizophrenia associated with microRNA alterations.
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DOI：
10.1371/journal.pone.0006121
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发表时间：
2009-07-01
期刊：
影响因子：
3.7
通讯作者：
Sommer SS
中科院分区：
文献类型：
--
作者：
Feng J;Sun G;Yan J;Noltner K;Li W;Buzin CH;Longmate J;Heston LL;Rossi J;Sommer SS
精神分裂症是一种严重的致残性脑部疾病，影响约1%的人口。单个microRNAs（miRNAs）影响基因表达的适度下调。此外，miRNA加工和/或功能所需的组分也与X连锁精神发育迟滞、神经和肿瘤疾病有关，表明miRNA广泛参与疾病。为了探索miRNAs在精神分裂症中的作用，X染色体上的59个microRNA基因在患有（193）和没有（191）精神分裂症谱系障碍的男性中被扩增和测序，以检验microRNA中的超罕见突变共同导致精神分裂症风险的假设。在这里，我们提供了microRNA基因功能障碍与精神分裂症的第一个关联。在4%的精神分裂症男性患者中，在8个不同的miRNA基因中鉴定出前体或成熟miRNA中的8个超罕见变体。在对照样本（有抑郁症史）中发现了一种超罕见变异（8/193 vs 1/191，单侧Fisher精确检验p=0.02，比值比= 8.2）。 在另外7，197条对照X染色体中没有发现这些变体。对变体miRNA前体的异位表达拷贝的功能分析表明功能丧失、功能获得或表达水平改变。虽然需要确认，但这项研究表明microRNA突变可能导致精神分裂症。
Schizophrenia is a severe disabling brain disease affecting about 1% of the population. Individual microRNAs (miRNAs) affect moderate downregulation of gene expression. In addition, components required for miRNA processing and/or function have also been implicated in X-linked mental retardation, neurological and neoplastic diseases, pointing to the wide ranging involvement of miRNAs in disease. To explore the role of miRNAs in schizophrenia, 59 microRNA genes on the X-chromosome were amplified and sequenced in males with (193) and without (191) schizophrenia spectrum disorders to test the hypothesis that ultra-rare mutations in microRNA collectively contribute to the risk of schizophrenia. Here we provide the first association of microRNA gene dysfunction with schizophrenia. Eight ultra-rare variants in the precursor or mature miRNA were identified in eight distinct miRNA genes in 4% of analyzed males with schizophrenia. One ultra-rare variant was identified in a control sample (with a history of depression) (8/193 versus 1/191, p = 0.02 by one-sided Fisher's exact test, odds ratio = 8.2). These variants were not found in an additional 7,197 control X-chromosomes. Functional analyses of ectopically expressed copies of the variant miRNA precursors demonstrate loss of function, gain of function or altered expression levels. While confirmation is required, this study suggests that microRNA mutations can contribute to schizophrenia.
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