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1.
Nestin最早发现于神经上皮干细胞,在肌肉和牙齿组织中也有表达。Nestin在中枢神经系统(central nervous system,CNS)中特异表达于神经前体细胞,其mRNA的减少与神经发育中干细胞的减少相平行,而且在神经系统病变和损伤的组织中有Nestin表达,表明Nestin可以作为研究神经系统发育的一个手段,对神经系统疾病的诊断也有一定的参考价值。 相似文献
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少突胶质细胞是中枢神经系统中形成髓鞘的高度特化的胶质细胞,由少突胶质前体细胞分化而来。长期以来,围绕少突胶质谱系细胞开展的研究主要集中在少突胶质细胞发育、髓鞘形成以及少突胶质谱系细胞在神经系统疾病中的作用等。新兴的单细胞转录组测序技术可以在转录组层面鉴定出特定类型细胞,为少突胶质谱系细胞的研究提供助力。本综述主要关注常见单细胞测序技术的发展以及它们在少突胶质细胞功能异质性和神经系统疾病研究中的应用,并对已取得的成果进行总结阐述,为单细胞测序技术在中枢神经系统疾病中少突胶质谱系细胞相关研究的应用和开发提供思路和参考。 相似文献
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目前有研究证实microRNA参与了神经系统生长发育和生理功能的调控,它也与可塑性障碍性疾病、神经系统退行性疾病、神经系统肿瘤、脑血管疾病等重大疾病的发生发展相关.随着microRNA研究领域的发展,一些重大神经系统疾病的相关发病机制将有可能被阐释. 相似文献
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氨基酰-tRNA合成酶(aminoacyl-tRNA synthetase, aaRS)催化tRNA氨基酰化反应与编校反应,合成正确的氨基酰-tRNA,为蛋白质生物合成提供原料。高等生物的aaRS获得了除蛋白质合成之外的非经典功能。近年来,随着基因组测序和外显子测序技术的发展和新增临床病例的发现,aaRS基因突变被报道与多种神经系统疾病相关。该文将简要介绍已报道的与aaRS基因突变相关的神经系统疾病,并总结aaRS基因突变导致神经系统疾病机制的研究进展;还将讨论神经系统疾病模型在aaRS非经典功能研究和新药设计中的潜在应用。 相似文献
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精神发育迟滞(旧称智力低下)作为儿科神经科常见的一组疾患,具有高度的遗传和表型异质性,大约25%~50%的精神发育迟滞是由遗传因素引起的,其中X染色体基因/基因组变异占25%~30%,导致X连锁的精神发育迟滞。X连锁的精神发育迟滞患者占所有精神发育迟滞患者的10%~15%以上,约20%~25%的男性精神发育迟滞归因于X连锁的精神发育迟滞。精神发育迟滞男女患病比例为1.3:1,这与男性只有一条X染色体的遗传背景有关。随着新一代基因组检测技术的快速发展和临床应用,尤其是全外显子测序、高深度测序、X染色体深度测序和全基因组芯片杂交,这些大大改善了精神发育迟滞患者的X染色体基因/基因组变异检出。本文综述了致精神发育迟滞的X染色体基因组/基因变异特点、其对男性精神发育迟滞的致病性,以及如何采用新测序技术提高检出率,旨在促进科研人员认识X染色体变异在男性精神发育迟滞的致病性,拓宽精神发育迟滞遗传病因的认识,同时也为遗传咨询和产前诊断提供理论依据。 相似文献
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趋化因子及其受体在神经系统发育中的作用 总被引:2,自引:0,他引:2
趋化因子是具有趋化作用的一类细胞因子,参与白细胞迁移的调控,在炎症中诱导性表达,与炎症过程密切相关,最初的研究主要局限于免疫系统。近几年来研究发现,趋化因子不仅参与神经系统疾病的炎症过程,而且在神经细胞成熟、发育等生理情况下组成性表达,发挥重要的生理调节作用,这一有趣的现象日益成为关注的焦点。本文主要针对趋化因子及其受体在神经系统发育中的作用及相关机制的研究成果予以综述,将有助于深入理解趋化因子与神经系统发育的关系,为进一步的研究提供依据。 相似文献
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DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further. 相似文献
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Muhammad Imran Naseer Angham Abdulrahman Abdulkareem Osama Yousef Muthaffar Adeel G. Chaudhary 《Saudi Journal of Biological Sciences》2021,28(5):2824-2829
RTTN (Rotatin) (OMIM 614833) is a large centrosomal protein coding gene. RTTN mutations are responsible for syndromic forms of malformation of brain development, leading to polymicrogyria, microcephaly, primordial dwarfism, seizure along with many other malformations. In this study we have identified a compound heterozygous mutation in RTTN gene having NM_173630 c.5225A > G p.His1742Arg in exon 39 and NM_173630 c.6038G > T p.Cys2013Phe in exon 45 of a consanguineous Saudi family leading to brain malformation, seizure, developmental delay, dysmorphic feature and microcephaly. Whole exome sequencing (WES) techniques was used to identify the causative mutation in the affected members of the family. WES data analysis was done and obtained data were further confirmed by using Sanger sequencing analysis. Moreover, the mutation was ruled out in 100 healthy control from normal population. To the best of our knowledge the novel compound heterozygous mutation observed in this study is the first report from Saudi Arabia. The identified compound heterozygous mutation will further explain the role of RTTN gene in development of microcephaly and neurodevelopmental disorders. 相似文献
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Natalie Saini Camille K. Giacobone Leszek J. Klimczak Brian N. Papas Adam B. Burkholder Jian-Liang Li David C. Fargo Re Bai Kevin Gerrish Cynthia L. Innes Shepherd H. Schurman Dmitry A. Gordenin 《PLoS genetics》2021,17(1)
Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual. Mutagenesis in human skin cells can be also caused by endogenous DNA damage and by DNA replication errors. The contributions of these processes to the somatic mutation load in the skin of healthy humans has so far not been accurately assessed because the low numbers of mutations from current sequencing methodologies preclude the distinction between sequencing errors and true somatic genome changes. In this work, we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages. We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells. We demonstrate that UV-induced base substitutions, insertions and deletions are prominent even in sun-shielded skin. In addition, we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as insertions and deletions characteristic of DNA replication errors in these cells. The endogenously induced somatic mutations and indels also demonstrate a linear increase with age, while UV-induced mutation load is age-independent. Finally, we show that DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells. Thus, somatic mutations in skin of healthy individuals reflect the interplay of environmental and endogenous factors in facilitating genome instability and carcinogenesis. 相似文献
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Martin L?wer Bernhard Y. Renard Jos de Graaf Meike Wagner Claudia Paret Christoph Kneip ?zlem Türeci Mustafa Diken Cedrik Britten Sebastian Kreiter Michael Koslowski John C. Castle Ugur Sahin 《PLoS computational biology》2012,8(9)
Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. 相似文献
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Kurek KC Luks VL Ayturk UM Alomari AI Fishman SJ Spencer SA Mulliken JB Bowen ME Yamamoto GL Kozakewich HP Warman ML 《American journal of human genetics》2012,90(6):1108-1115
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations. 相似文献
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Brahim Tabarki Fuad Al Mutairi Amal Al Hashem 《Experimental biology and medicine (Maywood, N.J.)》2015,240(3):400-402
WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy resistance. Recent studies demonstrate the growing role of WWOX gene in other human pathologies such as metabolic and nervous system-related conditions. The neurologic phenotype of WWOX mutation includes seizures, ataxia, developmental delay, and spasticity of variable severity. WWOX is a ubiquitous protein with high expression in many tissues including brain, cerebellum, brain stem, and spinal cord. WWOX is highly expressed in different brain regions during murine fetal development and remained unchanged in the cortex and the corpus callosum in adult mice. The mechanism or the putative role of WWOX in the nervous system is still unclear but may include abnormal signaling protein, disruption of neuronal pathways, neuronal differentiation, mitochondrial dysfunction, or apoptosis. Homozygous mutations affecting WWOX in humans are likely to be more described in the future using exome sequencing. The described findings highlight that WWOX plays a critical role in normal central nervous system development and disease.The aim of this review is to summarize the roles of WWOX in the developing brain. 相似文献
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Lili Hao Shanshan Li Duan Ma Shiyu Chen Bowen Zhang Deyong Xiao Jin Zhang Nan Jiang Shayi Jiang Jing Ma 《Journal of cellular and molecular medicine》2019,23(6):4454-4463
Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia disorder. ANK1 mutations account for most HS cases, but pathogenicity analysis and functional research have not been widely performed for these mutations. In this study, in order to confirm diagnosis, gene mutation was screened in two unrelated Chinese families with HS by a next‐generation sequencing (NGS) panel and then confirmed by Sanger sequencing. Two novel heterozygous mutations (c.C841T, p.R281X and c.T290G, p.L97R) of the ANK1 gene were identified in the two families respectively. Then, the pathogenicity of the two new mutations and two previously reported ANK1 mutations (c.C648G, p.Y216X and c.G424T, p.E142X) were studied by in vitro experiments. The four mutations increased the osmotic fragility of cells, reduced the stabilities of ANK1 proteins and prevented the protein from localizing to the plasma membrane and interacting with SPTB and SLC4A1. We classified these four mutations into disease‐causing mutations for HS. Thus, conducting the same mutation test and providing genetic counselling for the two families were meaningful and significant. Moreover, the identification of two novel mutations enriches the ANK1 mutation database, especially in China. 相似文献
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《Saudi Journal of Biological Sciences》2020,27(11):3125-3131
Intellectual developmental disorder with abnormal behavior, microcephaly and short stature (IDDABS), (OMIM# 618342) is an autosomal recessive condition described as developmental delay, poor or absent speech, intellectual disability, short stature, mild to progressive microcephaly, delayed psychomotor development, hyperactivity, seizure, along with mild to swear aggressive behavior. Homozygous frameshift mutation in Pseudouridine Synthase 7, Putative; (PUS7) OMIM# 616,261 NM_019042.3 and splice acceptor variants in Alpha-Aminoadipic Semialdehyde Synthase; (AASS) OMIM# 605,113 NM_005763.3 was funded. Whole exome sequencing (WES) technique was used as tool to identify the molecular diagnostic test. Different bioinformatics analysis done for WES data and we identified two novel mutations one as frameshift mutation c.606_607delGA, p.Ser282CysfsTer9 in the PUS7 gene and splice acceptor variants c.1767–1 G > A in the AASS gene has been reported. The pattern of family segregation maintained the pathogenicity of this variation associated with abnormal behavior, intellectual developmental disorder, microcephaly along with short stature IDDABS. Further, the WES data was validated in the family having other affected individuals and healthy controls (n = 100) was done using Sanger sequencing. Finally, our results further explained the role of WES in the disease diagnosis and elucidated that the mutation in PUS7 and AASS genes may lead an important role for the development of IDDABS in Saudi family. 相似文献
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Winter J Lehmann T Suckow V Kijas Z Kulozik A Kalscheuer V Hamel B Devriendt K Opitz J Lenzner S Ropers HH Schweiger S 《Human genetics》2003,112(3):249-254
Opitz G/BBB syndrome is a malformation syndrome of the ventral midline mainly characterized by hypertelorism, swallowing difficulties, hypospadias and developmental delay. SSCP analysis and genomic sequencing of the MID1 open reading frame have identified mutations in 80% of the families with X-linked inheritance. However, in many patients the underlying genetic defect remains undetected by these techniques. Using RNA diagnostics we have now identified a duplication of the MID1 first exon in a patient with X-linked Opitz G/BBB syndrome. This duplication introduces a premature termination codon. In addition, we could significantly lower the threshold for mutation detection on the DNA level by combining SSCP analysis with DHPLC technology. 相似文献
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Temperature modulation of DHPLC analysis for detection of coexisting constitutional and mosaic sequence variants in TSC2 总被引:2,自引:0,他引:2
Antonarakis ES Sampson JR Cheadle JP 《Journal of biochemical and biophysical methods》2002,51(2):161-164
Somatic mosaicism is a frequent phenomenon in Mendelian disorders that exhibit a high proportion of new mutations. However, mutant alleles present at low frequency may escape detection. We have previously shown that denaturing high-performance liquid chromatography (DHPLC) at the recommended melt temperature can detect TSC1 and TSC2 mutations in tuberous sclerosis patients with low-level somatic mosaicism, even when direct sequencing cannot identify the causative lesion. Here, we report the use of temperature modulation in DHPLC analysis to facilitate the robust detection of a mosaic mutation, N1643K, in the presence of a coexisting constitutional polymorphism. 相似文献