mutation

摘要： Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

摘要： Objective:Transcription factor GATA4 has significant roles in embryonic heart development.Mutations of GATA4 appear to be responsible for a wide variety of congenital heart defects(CHD).Despite the high prevalence of GATA4 mutations in CHD phenotypes,extensive studies have not been performed.The 3'-untranslated region(3'-UTR)of tho GATA4 gene comprises regulatory motifs and microRNA binding sites that are critical for the appropriate gene expression,nuclear transportation,and regulation of translation,and stability of mRNA.This study aimed to evaluate the association between mutations in the 3'-UTR of the GATA4 gene and CHD risk among Iranian patients.

摘要： BACKGROUND Solitary fibrous tumor(SFT)of the central nervous system is rare.It is predominantly benign and rarely malignant.There is no established standardized treatment regimen for malignant intracranial SFTs.CASE SUMMARY We present a rare case of SFT in a 9-year-old girl with a space-occupying effect in the frontal-parietal lobes.She underwent craniotomy,and the mass was resected.Immunohistochemistry examination of the specimen showed that Ki-67 proliferation index staining was highly positive in 80%of tumor cells.Whole exome sequencing of the surgical tissue showed 38 somatic gene mutations and 1 gene amplification such as fibroblast growth factor receptor 4 or TP53.At 1.5 mo after surgery,head magnetic resonance imaging revealed that the tumor had recurred.The patient received 60 Gy and 30 fractions of intensity modulated radiotherapy.The patient then received anlotinib 8 mg po qd for 1-14 d of a 21 d cycle.Following this regimen,the patient achieved stable disease for>17 mo.Magnetic resonance imaging at 1.5 year after surgery showed that the tumor had not progressed.CONCLUSION This is the first reported case of SFT of the central nervous system treated with surgery,radiotherapy and anlotinib.This regimen may be an effective treatment option for malignant intracranial SFT patients.

摘要： BACKGROUND Crouzon syndrome(CS;OMIM 123500)is an autosomal dominant inherited craniofacial disorder caused by mutations in the fibroblast growth factor receptor 2(FGFR2)gene.CS is characterized by craniofacial dysostosis,exophthalmos,and facial anomalies with hypoplastic maxilla and relative mandibular prognathism.CASE SUMMARY Our report involves a 6-year-old fraternal twin boy with many caries in the oral cavity who presented with characteristic features of CS based on clinical and radiographic examinations along with Sanger sequencing.The fraternal girl did not show any abnormalities indicating CS.Carious teeth and poor oral hygiene were managed promptly through administering appropriate behavior guidance,orthodontic treatment was planned,and preventive procedures were described.CONCLUSION CS could occur in a fraternal twin caused by a de novo mutation of the FGFR2 gene.Oral hygiene instruction,preventive programs on oral hygiene,orthodontic treatment,and maxillary osteotomy were required for treatment.

摘要： Objective: T-cell lymphoblastic lymphoma(T-LBL) is an aggressive neoplasm of precursor T cells, however,detailed genome-wide sequencing of large T-LBL cohorts has not been performed due to its rarity. The purpose of this study was to identify putative driver genes in T-LBL.Methods: To gain insight into the genetic mechanisms of T-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with T-LBL.Results: We identified 32 putative driver genes using whole-exome sequencing in 41 T-LBL cases, many of which have not previously been described in T-LBL, such as Janus kinase 3(JAK3), Janus kinase 1(JAK1), Runtrelated transcription factor 1(RUNX1) and Wilms’ tumor suppressor gene 1(WT1). When comparing the genetic alterations of T-LBL to T-cell acute lymphoblastic leukemia(T-ALL), we found that JAK-STAT and RAS pathway mutations were predominantly observed in T-LBL(58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in T-ALL. Notably, besides notch receptor 1(NOTCH1), mutational status of plant homeodomain(PHD)-like finger protein 6(PHF6) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL.Conclusions: Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.

摘要： BACKGROUND Mutations in the aggrecan(ACAN)gene are identified in patients with:spondyloepiphyseal dysplasia,Kimberley type;short stature with advanced bone age(BA);in the presence or absence of heterozygous ACAN mutation-induced early-onset osteoarthritis and/or osteochondritis dissecans;and spondyloepimetaphyseal dysplasia,ACAN type.Heterozygous mutations contribute to spondyloepiphyseal dysplasia,Kimberley type(MIM#608361),which is a milder skeletal dysplasia.In contrast,homozygous mutations cause a critical skeletal dysplasia,which is called spondyloepimetaphyseal dysplasia,ACAN type(MIM#612813).Lately,investigations on exome and genome sequencing have shown that ACAN mutations can also lead to idiopathic short stature with or without an advanced BA,in the presence or absence of early-onset osteoarthritis and/or osteochondritis dissecans(MIM#165800).We herein reported a heterozygous defect of ACAN in a family with autosomal dominant short stature,BA acceleration,and premature growth cessation.CASE SUMMARY A 2-year-old male patient visited us due to growth retardation.The patient presented symmetrical short stature(height 79 cm,T(p.Gln291*)of ACAN,which was not yet reported in cases of short stature.This mutation was also detected in his father and paternal grandmother.According to the Human Gene Mutation Database,67 ACAN mutations are registered.Most of these mutations are genetically inheritable,and very few children with short stature are associated with ACAN mutations.To date,heterozygous ACAN mutations have been reported in approximately 40 families worldwide,including a few individuals with a decelerated BA.CONCLUSION Heterozygous c.871C>T(p.Gln291*)variation of the ACAN gene was the disease-causing variant in this family.Collectively,our newly discovered mutation expanded the spectrum of ACAN gene mutations.

摘要： BACKGROUND Ullrich congenital muscular dystrophy(UCMD)is one of the collagen-VI-related myopathies caused by mutations of COL6A1,COL6A2,and COL6A3 genes.Affected individuals are characterized by muscle weakness,proximal joint contracture,distal joint hyperlaxity,and progressive respiratory failure.There is currently no cure for UCMD.Here,we report the clinical manifestations and prenatal diagnosis of compound heterozygous mutations of the COL6A2 gene in a Chinese family with UCMD.CASE SUMMARY A 3-year-old boy,his 4-year-old brother,their parents,and a 20-wk-old fetus in the mother’s womb were included in the study.The brothers had the typical manifestations of the early-severe subtype:A delayed motor milestone(never walking independently),torticollis,scoliosis,proximal joint contracture,distal joint hyperextension,right hip joint dislocation,and calcaneal protuberance.Both brothers were found by whole-exome sequencing and Sanger sequencing to carry two mutations of the COL6A2 gene(c.1353_c.1354insC,p.Arg453Profs-Ter42/c.2105G>A,p.Trp702Ter).The absence of collagen VI staining in the younger brother’s muscle was identified accurately.Genetic counseling and prenatal diagnosis were crucial for the family,as the autosomal recessive genetic disease affected a quarter of the patient’s siblings.The fetus of the mother’s third child underwent prenatal diagnosis and carried the same two mutations of COL6A2,confirmed in the amniotic fluid by multiplex ligation-dependent probe amplification and short tandem repeats.After a painful psychological struggle,the parents finally decided to terminate the pregnancy.CONCLUSION We report a Chinese family suffering from UCMD.By clarifying the COL6A2 mutations in the probands,the parents had the opportunity to opt for voluntary interruption of the third UCMD pregnancy.

摘要： BACKGROUND Herein,we report the genetic,clinical,molecular and biochemical features of two Han Chinese pedigrees with suggested maternally transmitted non-syndromic hearing loss.AIM To investigate the pathophysiology of hearing loss associated with mitochondrial tRNA mutations.METHODS Sixteen subjects from two Chinese families with hearing loss underwent clinical,genetic,molecular,and biochemical evaluations.Biochemical characterizations included the measurements of tRNA levels using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects.RESULTS Three of the 16 matrilineal relatives in these families exhibited a variable seriousness and age-at-onset(8 years)of deafness.Analysis of mtDNA mutation identified the novel homoplasmic tRNA^(Ile) 4268T>C mutation in two families both belonging to haplogroup D4j.The 4268T>C mutation is located in a highly conserved base pairing(6U–67A)of tRNA^(Ile).The elimination of 6U–67A basepairing may change the tRNA^(Ile) metabolism.Functional mutation was supported by an approximately 64.6%reduction in the level of tRNA^(Ile) observed in the lymphoblastoid cell lines with the 4268T>C mutation,in contrast to the wild-type cell lines.The reduced level of tRNA was below the proposed threshold for normal respiration in lymphoblastoid cells.However,genotyping analysis did not detect any mutations in the prominent deafness-causing gene GJB2 in any members of the family.CONCLUSION These data show that the novel tRNA^(Ile) 4268T>C mutation was involved in maternally transmitted deafness.However,epigenetic,other genetic,or environmental factors may be attributed to the phenotypic variability.These findings will be useful for understanding families with maternally inherited deafness.

摘要： Background: This study is aimed towards an exploration of mutant genes in primary liver cancer (PLC) patients by using bioinformatics and data mining techniques. Methods: Peripheral blood or paraffin-embedded tissues from 8 patients with PLC were analyzed using a 551 cancer-related gene panel on an Illumina NextSeq500 Sequencer (Illumina). Meanwhile, the data of 396 PLC cases were downloaded from The Cancer Genome Atlas (TCGA) database. The common mutated genes were obtained after integrating the mutation information of the above two cohorts, followed by functional enrichment and protein-protein interaction (PPI) analyses. Three well-known databases, including Vogelstein’s list, the Network of Cancer Gene (NCG), and the Catalog of Somatic Mutations in Cancer (COSMIC) database were used to screen driver genes. Furthermore, the Chi-square and logistic analysis were performed to analyze the correlation between the driver genes and clinicopathological characteristics, and Kaplan-Meier (KM) method and multivariate Cox analysis were conducted to evaluate the overall survival outcome. Results: In total, 84 mutation genes were obtained after 8 PLC patients undergoing gene mutation detection with next-generation sequencing (NGS). The top 100 most mutate gene data from PLC patients in TCGA database were downloaded. After integrating the above two cohorts, 17 common mutated genes were identified. Next, 11 driver genes were screened out by analyzing the intersection of the 17 mutation genes and the genes in the three well-known databases. Among them, RB1, TP53, and KRAS gene mutations were connected with clinicopathological characteristics, while all the 11 gene mutations had no relationship with overall survival. Conclusion: This study investigated the mutant genes with significant clinical implications in PLC patients, which may improve the knowledge of gene mutations in PLC molecular pathogenesis.

摘要： [Objective] To analyze the mutation signature and regularity of STR locus on 23 autosomes in paternity testing cases in Hainan. [Methods] A total of 2715 paternity testing cases accepted by the Forensic Medical Identification Centre of our hospital from 2017 to 2020 derived from counties and cities in Hainan Province were collected, the cases containing gene mutations were selected, the mutation rate and details of each locus were counted, and the mutation regu-larity of 23 STR loci was analyzed. [Results] Of the 2715 cases identified as “support”, 1487 were triplet cases and 1640 were dyad cases, totaling 4614 meioses;There were 50 gene mutation events (including 17 triplet mutations and 33 dyad mutations), with an average mutation rate of 0.0047% and a cumulative mutation rate of 1.0837%. A total of 19 of the 23 STR loci were mutated, with a mutation rate of 0.1301% at the D12S391 locus and 0.0217% at five loci, TPOX, D1S1656, D2S441, D22S1045, and PentaD, while no muta-tion events were found at four loci, D19S433, TH01, D13S317, and D7S820. Of the 50 mutation events, 47 were one-step mutations, 1 was two-step, and 2 were three-step. There were 35 paternal mutations (13 triplets and 22 dyads), 6 maternal mutations (4 triplets and 2 dyads), and 9 indeterminate pater-nal/maternal mutations, with a paternal to maternal mutation ratio of 5.83:1. [Conclusion] The mutation rate of D12S391 locus is the highest, and the muta-tion rate of TPOX, D1S1656, D2S441, D22S1045 and PentaD loci is the lowest in Hainan population, and paternal mutations are more than maternal muta-tions. In the paternity test, if 1 - 3 STR loci do not conform to the genetic law, especially when the mutant locus is homozygous or the next of kin is identi-fied, it is necessary to use other kits to review and increase the number of loci or use the second-generation sequencing technology to confirm, carefully de-termine the mutation and ensure the accuracy of the identification conclusion.

摘要： 本发明公开一种基于Hive Mutation API进行数据更新的方法,涉及数据更新技术领域；创建Mutator客户端，连接到Hive metastore，创建数据更新事务，计算需要更新的数据，读取虚拟主键，对需要写入的更新数据进行排序，获取原始数据与需要写入的更新数据合并为新的更新数据，调用接口进行数据更新，与现有技术相比，提高了Hive数据更新的性能，摆脱了Hive更新时需要删除原数据再重新导入的状况。