| 1 | Biochem. Soc. Trans. 2010 Apr 38: 445-51 |
|---|---|
| PMID | 20298200 |
| Title | Confirmed rare copy number variants implicate novel genes in schizophrenia. |
| Abstract | 了解包括学习，记忆，决策和构思在内的认知过程是如何由基因组编码的，这是生物学的关键问题。识别人类精神障碍基因的基因集是通往这一目标的途径。schizophrenia是一种具有认知症状，高遗传力和复杂遗传学的常见疾病。我们已经确定了涉及的基因schizophrenia通过测量91中整个基因组中DNA拷贝数的差异schizophrenia苏格兰人口中的病例和92个控制。我们的数据重现了> 3000的公共领域数据中观察到的稀有和常见变体schizophreniacases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A),CYFIP1[cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model ofschizophrenia和cognition is a major unanswered challenge. |
| SCZ Keywords | schizophrenia |
| 2 | Neuron 2013 9月79日：1169-82 |
| PMID | 24050404 |
| Title | CYFIP1coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. |
| Abstract | 这CYFIP1/SRA1基因位于与各种神经系统疾病有关的染色体区域，包括智力障碍，自闭症和schizophrenia。CYFIP1在两个明显无关的过程中起双重作用，抑制局部蛋白质的合成并有利于肌动蛋白重塑。在这里，我们表明脑衍生的神经营养因子（BDNF）驱动的突触信号释放CYFIP1from the translational inhibitory complex, triggering translation of target mRNAs and shiftingCYFIP1into the WAVE regulatory complex. Active Rac1 alters theCYFIP1conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes.CYFIP1thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. TheCYFIP1Interactome揭示了许多与脑部疾病相关的相互作用者，开辟了新的观点，以定义由脊柱畸形发生特征的神经系统障碍共享的调节途径。 |
| SCZ Keywords | schizophrenia |
| 3 | 世界J精神病学2013年9月3日：57-61 |
| PMID | 24255876 |
| Title | New findings in the genetics of schizophrenia. |
| Abstract | New findings inschizophreniagenetics are based on genome-wide association studies (GWAS), research into DNA copy number variations (CNVs), and endophenotypes. More than 70 genes have recently been suspected to be involved in the genetic background ofschizophreniabased on the GWAS�s results. They are typically related to neurodevelopment/neuroplasticity, immunology and neuroendocrinology. Nevertheless, for many detected genes their possible relationship toschizophreniaetiopathogenesis is still unknown. The CNVs at genome loci 1q21.1 (candidate gene e.g., PRKAB2), 2p16.3 (candidate gene e.g., NRXN1), 3q29 (candidate genes e.g., BDH1, DLG1, PAK2 or TFRC), 15q11.2 (candidate gene e.g.,CYFIP1), 15q13.3 (candidate gene e.g., CHRNA7), 16p13.1 (candidate genes e.g.,NTAN1 or NDE1) and 22q11.2 (candidate genes e.g., COMT, GSTT2 or PRODH) were associated withschizophrenia最常用。遗传研究beplay苹果手机能用吗schizophreniaendophenotypes, usually neurophysiological, neuromotoric, neurocognitive, neuroanatomical, neurological or personality-related, will help us to discover the role of relevant genes in the pathogenesis ofschizophrenia。还必须将其他研究平台的知识整合在beplay苹果手机能用吗schizophrenia，例如表观遗传学，基因环境相互作用，转录组学，蛋白质组学，代谢组学，神经影像学和心理病理学的研究。更好地了解schizophrenia可能导致治疗，预防和遗传咨询的变化。它还可能减少这种严重的精神障碍的污名。 |
| SCZ Keywords | schizophrenia |
| 4 | 是。J. Med。基因。2013年11月161A：2846-54 |
| PMID | 24123946 |
| Title | Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example. |
| Abstract | 近年来，已经确定了几种经常性拷贝数变化（CNV），这些变化已鉴定出神经发育障碍风险（例如，DEL和DUP和DUP 16P11.2，DEL15Q13.3，DEL和DUP 1Q21.1，DEL16P13.3，del16p13.3，del15q11.2）。它们通常是从未受影响的父母那里继承的，并且缺乏表型特异性。尽管关联研究的证据越来越多地将其视为易感性CNV，但它们的临床实用性却是有争议的。然而，临床医生经常受到挑战，要处理这些咨询情况，没有准则或共识。在本报告中，讨论了咨询问题和研究机会，以及经常性的15q11.2 bp1-bbeplay苹果手机能用吗p2（包括CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability,schizophrenia，癫痫和ASD。在本报告中，我们讨论了患者特异性和特定于家庭的信息如何改变对DEL15Q11.2的解释，这是对实际咨询情况中疾病的促成因素。此外，还提供了一项比利时佛兰德队列中ASD的关联研究，以及报告的关联研究，DEL15Q11.2的临床报告和基因组数据的概述。 |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr Bull 2013 5月39日：712-9 |
| PMID | 22317777 |
| Title | 15q11.2处的罕见CNV和TAG SNP与汉族人口中的精神分裂症有关。 |
| Abstract | Rare copy number variations (CNVs) were involved in the etiology of neuropsychiatric disorders, and some of them appeared to be shared risk factors for several different diseases. One of those promising loci is the CNV at 15q11.2, including 4 genes, TUBGCP5,CYFIP1, NIPA2, and NIPA1. Several studies showed that microdeletions at this locus were significant associated withschizophrenia。在当前的研究中，我们研究了稀有的CNV和公共单核苷酸多态性（SNP）在15q11.2 In In In In的作用。schizophreniain the Chinese Han population. We screened deletions at 15q11.2 in 2058schizophreniapatients and 3275 normal controls in Chinese Han population by Affymetrix 500K/6.0 SNP arrays and SYBR green real-time polymerase chain reaction and then validated deletions by multiplex ligation-dependent probe amplification and Taqman real-time assays. We successfully genotyped 27 tag SNPs in total and tested associations in 1144schizophreniacases and 1144 normal controls. 我们发现，在对照组中，缺失的三重增加，OR = 4.45（95％CI = 1.36-14.60）和p = .014。在对普通SNP的分析中，我们发现最重要的SNPschizophrenia为RS4778334（OR = .72，95％CI = 0.60-0.87，排列后的等位基因P = .0056，置换后的基因型P = .015）。我们还发现了SNP RS1009153CYFIP1与之相关schizophrenia(OR=0.82, 95% CI=0.73-0.93, allelic P=.044 after permutation). We found that both rare deletions and common variants at 15q11.2 were associated withschizophreniain the Chinese Han population. |
| SCZ Keywords | schizophrenia |
| 6 | Schizophr Bull 2014 Nov 40: 1285-99 |
| PMID | 24664977 |
| Title | Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes. |
| Abstract | schizophreniais a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts thatschizophrenia部分归因于常见的遗传变异。但是，最近的研究清楚地表明，拷贝数变化（CNV）在schizophreniasusceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk ofschizophrenia。通过使用累积评分，我们系统地优先考虑受CNV影响的基因schizophrenia。We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9,CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with knownschizophreniasusceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated withschizophrenia。进一步的蛋白质 - 蛋白质相互作用（PPI）分析表明，受CNV影响的基因的蛋白质产物经常与已知相互作用schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies keyschizophreniacandidate genes. Our results provide a global overview of genes impacted by CNVs inschizophrenia并揭示了从头cnvs的密集互连分子网络schizophrenia。Though the prioritized top genes represent promisingschizophrenia风险基因，采用不同优先级方法的进一步工作和独立样本以确认这些发现。然而，确定的关键候选基因可能在schizophrenia，这些基因的进一步功能表征可以为将来的治疗和诊断提供关键靶标。 |
| SCZ Keywords | schizophrenia |
| 7 | Transl Psychiatry 2014 -1 4: e374 |
| PMID | 24667445 |
| Title | 这autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines. |
| Abstract | Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such asschizophrenia（SCZ）和自闭症谱系障碍（ASD）。然而，在该基因座上的基因在神经系统发展，功能和连通性中的个体作用仍然知之甚少。该地区一个基因的单倍不足，CYFIP1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that alteringCYFIP1神经元的表达水平在体外和体内都会影响树突的复杂性，脊柱形态，脊柱肌动蛋白动力学和突触？-AMINO-3-羟基-5-甲基-4-甲基-4-异沙唑嗜酸果酸（AMPA）受体横向扩散。CYFIP1is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived fromCYFIP1heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly,CYFIP1在CYFIP1haploinsufficient neurons. In vivo,CYFIP1heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation ofCYFIP1表达水平导致CNS成熟和神经元连通性的病理变化，这两者都可能有助于ASD和SCZ中看到的神经系统症状的发展。 |
| SCZ Keywords | schizophrenia |
| 8 | Cell Stem Cell 2014 Jul 15: 79-91 |
| PMID | 24996170 |
| Title | Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. |
| Abstract | Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors forschizophrenia和autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency ofCYFIP1, a gene within 15q11.2 that encodes a subunit of the�WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency inCYFIP1和WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction betweenCYFIP1和中介ACTR2波信号和风险schizophrenia。我们的发现提供了有关如何CYFIP1调节神经干细胞功能，并可能导致神经精神疾病的敏感性。 |
| SCZ Keywords | schizophrenia |
| 9 | Proc. Natl. Acad. Sci. U.S.A. 2014 Jan 111: 361-6 |
| PMID | 24368850 |
| Title | OHNOLOLS在致病拷贝数突变中的代表性过多。 |
| Abstract | 许多稀有拷贝数变体（CNV），包括删除和重复，都与发育障碍有关，包括schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study. |
| SCZ Keywords | schizophrenia |
| 10 | 摩尔。精神病学2015年9月20日：1069-78 |
| PMID | 25311365 |
| Title | Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. |
| Abstract | 在约1％的患有自闭症谱系障碍（ASD）的个体中，观察到15q11-13的罕见母体遗传重复，使其成为ASD最常见的原因之一。15q11-13包括一个复杂的区域，并且由于此拷贝数变化包含许多基因，因此探索单个基因型 - 表型关系很重要。细胞质FMR1相互作用蛋白1（CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions ofCYFIP1in patients withschizophrenia和智力残疾。在这里，我们确认CYFIP1is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increasedCYFIP1剂量可能易于神经发育疾病，我们研究了其在多个系统中过表达的结果。我们证明了这种过表达的CYFIP1导致形态异常，包括SY5Y细胞中的细胞肥大和分化的小鼠神经元祖细胞。我们通过生成BAC转基因小鼠来验证这些结果，该小鼠过表达CYFIP1在内源性启动子下，观察到成熟的树突状棘和树突状脊柱密度的比例增加。胚胎第15天的基因表达分析表明，雷帕霉素（MTOR）信号的哺乳动物靶标失调，这在蛋白质水平上得到了证实。重要的是，在15q11-13重复患者ASD的大脑中也观察到了类似的MTOR相关失调证据。最后，用MTOR抑制剂（雷帕霉素）处理分化的小鼠神经元祖细胞，从CYFIP1过表达。这些数据一起表明CYFIP1overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD. |
| SCZ Keywords | schizophrenia |
| 11 | Mol Neuropsychiatry 2015年7月1日：116-123 |
| PMID | 26528485 |
| Title | Genetic and morphological features of human iPSC-derived neurons with chromosome 15q11.2 (BP1-BP2) deletions. |
| Abstract | Copy number variation on chromosome 15q11.2 (BP1-BP2) causes deletion ofCYFIP1, NIPA1, NIPA2 and TUBGCP5; it also affects brain structure and elevates risk for several neurodevelopmental disorders that are associated with dendritic spine abnormalities. In rodents, alteredCYFIP1表达树突棘形态学变化,非常贴切ivating analyses of human neuronal cells derived from iPSCs (iPSC-neurons). IPSC是由母亲和她的后代产生的，均带有15q11.2（BP1-BP2）删除和非删除控制。使用定量实时PCR分析估算缺失区域中的基因表达。使用免疫细胞化学表征神经祖细胞（NPC）和IPSC-神经元。 CYFIP1, NIPA1, NIPA2 and TUBGCP5 gene expression was lower in iPSCs, NPCs and iPSC-neurons from the mother and her offspring in relation to control cells.CYFIP1和PSD95 protein levels were lower in iPSC-neurons derived from the CNV bearing individuals using Western blot analysis. At 10 weeks post-differentiation, iPSC-neurons appeared to show dendritic spines and qualitative analysis suggested that dendritic morphology was altered in 15q11.2 deletion subjects compared with control cells. 15 q11.2 (BP1-BP2)删除有关reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated altered iPSC-neuron dendritic morphology. |
| SCZ Keywords | schizophrenia |
| 12 | Int J Mol Sci 2015 -1 16：4068-82 |
| PMID | 25689425 |
| Title | 15q11.2 BP1-BP2微骨骼综合征：评论。 |
| Abstract | Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures,schizophrenia轻度畸形特征不太常见。15q11.2 BP1-BP2微骨骼涉及四个基因（即tubGCP5，CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ?75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%),schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. |
| SCZ Keywords | schizophrenia |
| 13 | PLOS ONE 2016 -1 11：E0148039 |
| PMID | 26824476 |
| Title | Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks. |
| Abstract | Deletions encompassing the BP1-2 region at 15q11.2 increaseschizophrenia和epilepsy risk, but only some carriers have either disorder. To investigate the role ofCYFIP1这是该区域内的一个基因，我们在BP1-2基因座处的每个基因的供体衍生的人类祖细胞进行了敲低实验。RNA-seq和细胞测定确定敲低CYFIP1损害细胞骨架重塑。FMRP靶标和突触后密度基因，每个基因与schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs).schizophrenia和/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role forCYFIP1in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation. |
| SCZ Keywords | schizophrenia |
| 14 | J. Neurosci. 2016 Feb 36: 1564-76 |
| PMID | 26843638 |
| Title | Cyfip1 Regulates Presynaptic Activity during Development. |
| Abstract | Copy number variations encompassing the gene encodingCYFIP1have been associated with a variety of human diseases, including autism andschizophrenia。Here we show that juvenile mice hemizygous forCYFIP1have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reducedCYFIP1水平可减少配对的脉冲促进，并增加微型EPSC频率而不会改变幅度。高分辨率检查表明，这些变化主要是由于突触前末端大小的增加和囊泡释放概率增强所致。短发夹介导的敲低CYFIP1与突变体的表达结合CYFIP1proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role forCYFIP1in the generation of normally functioning synapses and suggest a means by which changes inCYFIP1水平可能会影响神经网络的产生，并导致异常和适应不良的行为。 Several developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins.CYFIP1是一种这样的蛋白质，但是它在大脑发育中所发挥的作用知之甚少。我们问是否减少CYFIP1水平改变了发展突触的功能。数据显示突触减少CYFIP1are larger and release neurotransmitter more rapidly. These effects are due toCYFIP1在肌动蛋白聚合中的作用，并通过表达逆转CYFIP1突变蛋白保留肌动蛋白调节功能或抑制Rac1。因此，CYFIP1当活动有助于定义神经途径时，在发育阶段中具有更为突出的早期作用，可调节突触前活动。 |
| SCZ Keywords | schizophrenia |