A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia
A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia
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DOI：
10.1038/mp.2008.128
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发表时间：
2010-06-01
影响因子：
11
通讯作者：
Gurling, H. M. D.
中科院分区：
文献类型：
--
作者：
Datta, S. R.;McQuillin, A.;Gurling, H. M. D.
在伦敦大学学院 (UCL) 和美国的病例对照样本中，中心粒周围物质 1 基因 (PCM1) 的标记显示出与精神分裂症的遗传关联。在本文中，我们报告了来自阿伯丁的苏格兰大型病例对照样本中 PCM1 关联的统计显着复制。对继承了与精神分裂症相关的单倍型的研究志愿者的基因组 DNA 进行重新测序显示，外显子 24 中存在苏氨酸至异亮氨酸的错义突变，这可能会改变 PCM1 (rs370429) 的结构和功能。这种突变仅在 98 名精神分裂症研究对象和 2246 名病例和对照研究对象中的对照对象中作为杂合子被发现。在98名rs370429携带者中，67人患有精神分裂症。在伦敦和阿伯丁样本中，相同的等位基因和单倍型与精神分裂症相关。 PCM1 中另一个潜在的病因碱基对变化是 rs445422，它改变了剪接位点信号。电泳迁移率变动分析显示，进一步的突变 rs208747 可创建或破坏启动子转录因子位点。还发现了外显子中另外五个非同义变化。在伦敦大学学院病例对照样本中发现的新变异的基因分型强化了等位基因和单倍型关联的证据（P = 0.02-0.0002）。考虑到与精神分裂症相关的单倍型的数量和特性，PCM1 基因内部和周围必定存在进一步的病因学碱基对变化。 PCM1 蛋白已被证明可与精神分裂症破坏蛋白 1 (DISC1)、Bardet-Biedl 综合征 4 和亨廷顿蛋白相关蛋白 1 直接相互作用，并且对神经元细胞生长很重要。在另一项研究中，我们发现氯氮平而非氟哌啶醇下调了小鼠大脑中 PCM1 的表达。我们假设突变的 PCM1 可能通过中枢神经系统中分裂细胞的异常细胞分裂和异常再生导致精神分裂症的亚型。我们之前发现 PCM1 相关的精神分裂症患者存在眶额体积缺陷，而不是非 PCM1 相关的精神分裂症患者的颞极缺陷，这支持了这一点。在没有进一步的细胞生物学的情况下解释我们发现的突变的实际生物学效应时需要谨慎。然而，我们发现的 DNA 变化值得在多个病例对照人群中进行广泛的基因分型。分子精神病学 (2010) 15, 615-628; doi：10.1038/mp.2008.128； 2008 年 12 月 2 日在线发布
Markers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422, which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P = 0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, Bardet-Biedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations. Molecular Psychiatry (2010) 15, 615-628; doi: 10.1038/mp.2008.128; published online 2 December 2008