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Objective@#To evaluate the association of smoking with the risk of ankylosing spondylitis (AS) using a Mendelian randomization (MR) approach.@*Methods@#A total of 16 383 186 AS-associated single nucleotide polymorphisms (SNPs), 378 smoking initiation associated SNPs and 126 lifetime smoking score-associated SNPs were collected from three large-scale genome-wide association studies (GWAS). The association of smoking phenotypes with the risk of AS was examined using inverse-variance weighted (IVW) with AS as a outcome variable, smoking initiation and lifetime smoking score as exposure factors and SNPs with strong associations with smoking as instrumental variables, and sensitivity analyses were performed with maximum likelihood-based method, MR pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression analysis.@*Results@# A 33.5% increased risk of AS was found among genetically predicted smokers relative to non-smokers (OR=1.335, 95%CI: 1.059-1.682), and an increase in predicted lifetime smoking by per standard deviation resulted in a 101.4% increased risk of AS (OR=2.014, 95%CI: 1.341-3.024). The maximum likelihood-based method and MR-PRESSO test showed consistent correlated effect estimations and MR-Egger regression analysis identified no evidence of pleiotropy.@*Conclusion@#It is genetically predicted that smoking is associated with an increased risk of AS.
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Objective:To report the clinical features of KCNQ2-associated epilepsy and the novel mutations and unreported clinical phenotype of KCNQ2 gene, so as to provide help for treatment selection and prognosis evaluation.Methods:Among 979 patients with epilepsy and developmental delay who were admitted to the Department of Neurology,Children′s Hospital Affiliated to Capital Institute of Pediatrics from July 2015 to October 2019, a total of 13 patients were selected from 12 families with KCNQ2 gene mutation by whole exome sequencing technology. Suspected mutations were verified by Sanger sequencing on the probands and their parents to identify the source. The clinical phenotype and genotype were analyzed according to these results.Results:Among the 13 patients with epilepsy, the onset age of four cases were older than six months [two cases in infancy (epilepsy encephalopathy), one case in early childhood (epilepsy encephalopathy) and one case in adolescence (benign epilepsy)]. Eight cases were treated with oxcarbazepine, of whom five cases were seizure free, and two cases showed partial response (>50%). Two cases treated with topiramate were seizure free. Five novel mutations were found in this research, including c.379T>G(p.Y127D), c.1A>C(initial codon mutation), c.708G>C(p.W236C), c.1027G>T(p.A343S) and c.1649T>G(p.V550G).Conclusions:Although it was rare in clinical work, the variation of KCNQ2 gene existed in patients with childhood-onset epilepsy and adolescent-onset epilepsy. Meanwhile, five novel mutations of KCNQ2 gene were reported, which further expanded its gene spectrum. This research supported that oxcarbazepine was the efficient medicine for the KCNQ2-associated epilepsy. Genetic testing showed great help to the treatment of epilepsy.
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OBJECTIVE@#To explore the genetic basis for a pedigree affected with X-linked recessive mental retardation Claes-Jensen type.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the patient, his parents (phenotypically normal) and two elder brothers with similar clinical manifestations. Whole exome sequencing was carried out for the proband, and the result was verified by Sanger sequencing.@*RESULTS@#The proband was found to harbor a hemizygous c.1565C>T missense variant in exon 11 of the KDM5C gene. The transition has resulted in replacement of serine by phenylalanine at position 522 (p.Ser522Phe). Sanger sequencing showed that the patient's two elder brothers and mother carried the same variant, which was predicted to be probably damaging by SIFT, PolyPhen2 and Mutation_Taster. The three affected brothers presented with similar clinical phenotypes characterized by mental retardation, speech delay, behavioral problem, self-limited epilepsy responsible to medication, short stature and microcephaly. The mother only had mild cognitive impairment and learning disability. The same variant was not found in their father and was unreported previously.@*CONCLUSION@#The c.1565C>T (p.Ser522Phe) of the KDM5C gene probably underlay the X-linked recessive mental retardation Claes-Jensen type in this pedigree.
Subject(s)
Aged , Female , Humans , Male , Histone Demethylases/genetics , Mental Retardation, X-Linked/pathology , Mutation, Missense/genetics , Pedigree , Phenotype , Exome SequencingABSTRACT
Objective:To summarize the phenotype of mtDNA8344A>G and to explore the new phenotype.Methods:A family with mtDNA 8344A>G was retrospectively analyzed in the Children′s Hospital Affiliated to the Capital Institute of Pediatrics in April 2019. The clinical data of the proband and his mother were collected and summarized.Results:A four-year-old boy presented with rapidly progressing central respiratory failure and continuous mechanical ventilation, whose serum lactate levels fluctuated between 4.5 to 8.3 mmol/L. Linear abnormality signals from dorsal medulla to the first and second cervical spine were displayed on cranial magnetic resonance imaging. Ragged red fiber and ragged broken blue fibers, cytochrome C oxidase negative muscle fibers and enhanced vascular succinate dehydrogenase reaction were seen in muscle biopsy, accorded with the pathological characteristics of mitochondrial myopathy. The activity detection of respiratory chain enzyme complex in muscle tissues showed decreased activity of mitochondrial respiratory chain enzyme complex Ⅰ and complex Ⅳ. mtDNA 8344A>G mutation was detected in his peripheral blood lymphocyte and urine exfoliated epithelial cells. The proportion of mutations in his blood lymphocytes was 77.29%, and the proportion of mutations in his urothelial epithelial cells was 90.13%. His mother was 30 years old, thin in stature without obvious clinical symptoms and signs. The mutant mtDNA 8344A>G was also detected in her peripheral blood and urine. The mutant rate in her blood and urine was 77.29% and 90.13% respectively.Conclusions:A case of rapidly progressive central respiratory failure in children and his family are reported. Genetic testing showed mtDNA8344A>G mutation, and both muscle biopsy pathology and muscle tissue respiratory chain enzyme complex activity test results supported mitochondrial disease. By this case, the phenotype spectrum of the gene was expanded.
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Objective To analyze the clinical manifestation and genetic testing in a patient with Adams-Oliver syndrome (AOS) and summarize clinical and genetic characteristics of the dedicator of cytokinesis (DOCK) 6 gene related AOS through reviewing related references.Methods Information of the proband who was hospitalized in Affiliated Children Hospital of Capital Institute of Pediatrics in October 2016 and her family members as well as their DNA samples were collected.The gene sequencing was performed using next generation sequencing technology.Using "Adams-Oliver syndrome"and "DOCK6" as key words,the relevant articles were searched from the Pubmed,China National Knowledge Internet and Wanfang databases and reports of 19 cases were reviewed.Results The proband is an eight months old girl.She presented with severe developmental delay,terminal transverse limb defects and visual loss after birth,and then suffered from tonic seizures and myoclonic seizures at two months old.By physical examination she was found to have esotropia and visual loss.The distal phalanx and nail of the right second-fourth fingers were absent,while the phalangette of the left second-fourth fingers and bilateral distal phalanges of toes were short with small nails attachment.Thyroid function test showed hypothyroidism.The ocular fundus examination showed the residual vitreous artery in the left eye and the retinal pigment degeneration in the right eye.CT scan showed multiple bilateral periventricular calcification and cranial magnetic resonance imaging showed bilateral periventricular lesion.Two heterozygous mutations were identified in DOCK6 gene:one was a known pathogenic mutation (p.L1064Vfs*60),and the other was a novel splice site mutation (c.873+ 1G＞A).By analyzing this case and reported 19 cases,the common performances of DOCK6 gene related AOS included terminal transverse limb defects (20/20),aplasia cutis congenita (18/20),ocular abnormalities (13/20),seizures (12/20),mental retardation (12/20),microcephaly (10/20),cardiovascular malformations (10/20),intrauterine growth retardation (6/20).The mutation of the DOCK6 gene was found to be dominated by frameshift mutation and splice site mutation.Conclusions If either terminal transverse limb defects or aplasia cutis congenita was detected in a patient,AOS should be under consideration.In addition,autosomal recessive inheritance,nervous system and eyes involvement will further indicate DOCK6 gene related AOS.
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PURPOSE: Uridine-cytidine kinase (UCK) 2 is a rate-limiting enzyme involved in the salvage pathway of pyrimidine-nucleotide biosynthesis. Recent studies have shown that UCK2 is overexpressed in many types of cancer and may play a crucial role in activating antitumor prodrugs in human cancer cells. In the current study, we evaluated the potential prognostic value of UCK2 in breast cancer. METHODS: We searched public databases to explore associations between UCK2 gene expression and clinical parameters in patients with breast cancer. Gene set enrichment analysis (GSEA) was performed to identify biological pathways associated with UCK2 gene expression levels. Survival analyses were performed using 10 independent large-scale breast cancer microarray datasets. RESULTS: We found that UCK2 mRNA expression was elevated in breast cancer tissue compared with adjacent nontumorous tissue or breast tissue from healthy controls. High UCK2 levels were correlated with estrogen receptor negativity (p<0.001), advanced tumor grade (p<0.001), and poor tumor differentiation (p<0.001). GSEA revealed that UCK2-high breast cancers were enriched for gene sets associated with metastasis, progenitor-like phenotypes, and poor prognosis. Multivariable Cox proportional hazards regression analyses of microarray datasets verified that high UCK2 gene expression was associated with poor overall survival in a dose-response manner. The prognostic power of UCK2 was superior to that of TNM staging and comparable to that of multiple gene signatures. CONCLUSION: These findings suggest that UCK2 may be a promising prognostic biomarker for patients with breast cancer.
Subject(s)
Humans , Biomarkers , Breast Neoplasms , Breast , Dataset , Estrogens , Gene Expression , Neoplasm Metastasis , Neoplasm Staging , Phenotype , Prodrugs , Prognosis , RNA, Messenger , Uridine KinaseABSTRACT
Objective To explore the effects of aerobic exercise and resistance training on center arterial blood pressure.Methods Fifteen healthy men who had not practiced aerobic exercise or resistance training within the previous 6 months were enrolled in this study.A self-matched pairs design was adopted.All of the subjects performed moderate intensity aerobic exercise,for 30 min initially,and after 2 weeks,performed resistance training at 60％ of their l-repeat maximum effort (1-RM).Their central aortic systolic blood pressure (CSBP) before and after aerobic exercise and resistance training were measured and compared,respectively.The changes in CSBP and an augmentation index (AI) of radial artery and relative blood pressure were compared between the two interventions.Results CSBP decreased significantly after both sorts of training.The two types of training showed no significant difference in their effects on CSBP.However,after a 20 min recovery,systolic blood pressure and pulse pressure were significantly lower after aerobic exercise than after resistance training.The significant difference persisted after 20 min and 40 min of re-covery.The AI of the radial artery was also significantly lower 5 min after aerobic exercise than after resistance train-ing.Conclusions After moderate aerobic exercise and resistance training,CBSP,AI and systolic pressure all display favorable changes.However,moderate intensity aerobic exercise provides the better effect in improving blood pressure.
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<p><b>OBJECTIVE</b>To compare the efficiency of three different serotypes of adeno-associated virus (AAV) in mediating the transfection of enhanced green fluorescent protein (EGFP) in Tibet minipig fetal fibroblasts (PFFs).</p><p><b>METHODS</b>Three recombinant AAV of different serotypes encoding EGFP were constructed and transfected into primary cultured PFFs at the multiplicity of infection (MOI) ranging from 10(3) to 10(5). The expression rates of EGFP in the PFFs were assessed 72 h after the infection by flow cytometry, and the transfected PFFs were observed under inverted fluorescence microscope. The toxicity of AAVs to PFFs was analyzed using MTT assay.</p><p><b>RESULTS</b>The transfection efficiency of AAV2-EGFP increased with MOI. At the MOI of 10(3), the transfection efficiency of AAV2-EGFP was (33.68∓1.18)%, which increased to (50.80∓2.59)% at the MOI of 10(4) but without obvious further increase at the MOI of 10(5). The other two serotypes of the virus (AAV8 and AAV9) showed no obvious changes in the infection efficiency at any MOIs. The transfection efficiency of AAV8 was (8.3∓0.02)% and that of AAV9 was (2.20∓1.02)% at the MOI of 10(5). Transfection with the 3 viruses caused no adverse effects on the normal cell growth of the PFFs.</p><p><b>CONCLUSIONS</b>AAV2 has a significantly higher infection rate in cultured PFFs than AAV8 and AAV9, and the latter two have a rather low infection efficiency. All the three AAVs have no cell toxicity to the PFFs.</p>