BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to ...BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.展开更多
Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvest...Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.展开更多
Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-ons...Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.展开更多
Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,...Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,and epigenetic levels.LncRNAs play important roles in various biological processes such as dosage compensation,genomic imprinting,cell cycle regulation,and cell differentiation.Although their characterizations have been relatively straightforward with recent advances in modern biology,the functions of lncRNAs are largely unknown.Herein,we discuss the biological functions and research methods of lncRNAs.展开更多
Congenital heart disease(CHD)is the most common birth defect worldwide.Long non-coding RNAs(lncRNAs)have been implicated in many diseases.However,their involvement in CHD is not well understood.This study aimed to inv...Congenital heart disease(CHD)is the most common birth defect worldwide.Long non-coding RNAs(lncRNAs)have been implicated in many diseases.However,their involvement in CHD is not well understood.This study aimed to investigate the role of dysregulated lncRNAs in CHD.We used Gene Expression Omnibus data mining,bioinformatics analysis,and analysis of clinical tissue samples and observed that the novel lncRNA SAP30-2:1 with unknown function was significantly downregulated in damaged cardiac tissues from patients with CHD.Knockdown of lncRNA SAP30-2:1 inhibited the proliferation of human embryonic kidney and AC16 cells and decreased the expression of heart and neural crest derivatives expressed 2(HAND2).Moreover,lncRNA SAP30-2:1 was associated with HAND2 by RNA immunoprecipitation.Overall,these results suggest that lncRNA SAP30-2:1 may be involved in heart development through affecting cell proliferation via targeting HAND2 and may thus represent a novel therapeutic target for CHD.展开更多
Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essent...Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essential for their biosynthetic and bioenergetic functions.Cancer cells with mutations in isocitrate dehydrogenase 1(IDH1)exhibit differentiation arrest,epigenetic and transcriptional reprogramming,and sensitivity to mitochondrial OXPHOS inhibitors.In this study,we report that berberine,which is widely used in China to treat intestinal infections,acted solely at the mitochondrial electron transport chain(ETC)complex I,and that its association with IDH1 mutant inhibitor(IDH1^(m)i)AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro and in vivo.Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia(AML)patients using combinatory mitochondrial targeted medicines,particularly those who are resistant to or relapsing from IDH1m i.展开更多
Background After the implementation of the universal two-child policy in China,it was more frequent to have long interpregnancy intervals(IPIs)and advanced maternal age.However,the interactions between long IPIs and a...Background After the implementation of the universal two-child policy in China,it was more frequent to have long interpregnancy intervals(IPIs)and advanced maternal age.However,the interactions between long IPIs and advanced maternal age on neonatal outcomes are unknown.Methods The study subjects of this historical cohort study were multiparas with singleton live births between October 1st,2015,and October 31st,2020.IPI was defned as the interval between delivery and conception of the subsequent pregnancy.Logistic regression models were used to calculate adjusted odds ratios(aORs)and 95%confdence intervals(CIs)of the risks of preterm birth(PTB),low birth weight(LBW),small for gestation age,and 1-min Apgar score≤7 in diferent IPI groups.Relative excess risk due to interaction(RERI)was used to evaluate the additive interaction between long IPIs and advanced maternal age.Results Compared with the 24≤IPI≤59 months group,the long IPI group(IPI≥60 months)was associated with a higher risk of PTB(aOR,1.27;95%CI:1.07–1.50),LBW(aOR,1.32;95%CI 1.08–1.61),and one-minute Apgar score≤7(aOR,1.46;95%CI 1.07–1.98).Negative additive interactions(all RERIs<0)existed between long IPIs and advanced maternal age for these neonatal outcomes.Meanwhile,IPI<12 months was also associated with PTB(aOR,1.51;95%CI 1.13–2.01),LBW(aOR,1.50;95%CI 1.09–2.07),and 1-min Apgar score≤7(aOR,1.93;95%CI 1.23–3.04).Conclusions Both short and long IPIs are associated with an increased risk of adverse neonatal outcomes.Appropriate IPI should be recommended to women planning to become pregnant again.In addition,better antenatal care might be taken to balance the inferiority of advanced maternal age and to improve neonatal outcomes.展开更多
As a potential cost-effective feedstock for highly efficient fermentation of glycerol and its downstream product 1,3-propanediol(1,3-PD),duckweed starch was characterized and used for glycerol fermentation,for the fir...As a potential cost-effective feedstock for highly efficient fermentation of glycerol and its downstream product 1,3-propanediol(1,3-PD),duckweed starch was characterized and used for glycerol fermentation,for the first time,in this study.Genes involved in glycerol biosynthesis(gpd1 and gpp2)were overexpressed in Escherichia coli,and genes involved in glycerol catabolism(glpK and gldA)were disrupted,which led to significantly decreased residual sugar levels and dramatically increased glycerol production.The maximum glycerol concentration in fed-batch fermentation reached 102.72 g L^(-1) at 28 h,and the glycerol productivity was 3.67 g L^(-1) h^(-1),which,to our knowledge,is the highest productivity thus far reported.Subsequently,glycerol broth was fermented into 1,3-PD by Klebsiella pneumoniae.The concentration,conversion rate and productivity of 1,3-PD reached 35.54 g L^(-1),40.28%and 0.89 g L^(-1) h^(-1),respectively,without optimization.In summary,the duckweed starch-to-glycerol-to-1,3-PD process is feasible and shows potential for improving glycerol industry competitiveness.展开更多
基金Supported by The Science and Technology Department of Sichuan Province,No.2021JDKP0015.
文摘BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.
基金This work was supported by an Institute for Information and CommunicationsTechnology Promotion (IITP) grant funded by the Korean Government (MSIT) (2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.
基金This work was supported by an Institute for Information and Communications Technology Promotion(IITP)grant funded by the Korean government(MSIT)(2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.
文摘Long noncoding RNAs(lncRNAs)are functional RNA molecules which are longer than 200 nucleotides in length that do not encode proteins;instead,they regulate target gene expression at transcriptional,posttranscriptional,and epigenetic levels.LncRNAs play important roles in various biological processes such as dosage compensation,genomic imprinting,cell cycle regulation,and cell differentiation.Although their characterizations have been relatively straightforward with recent advances in modern biology,the functions of lncRNAs are largely unknown.Herein,we discuss the biological functions and research methods of lncRNAs.
基金supported by grants from the National Key Research and Development Program of China(No.2016YFC1000500)the National Science Foundation for Young Scientists(No.81801501)the Postdo ctoral Science Foundation of China(No.2018M632026).
文摘Congenital heart disease(CHD)is the most common birth defect worldwide.Long non-coding RNAs(lncRNAs)have been implicated in many diseases.However,their involvement in CHD is not well understood.This study aimed to investigate the role of dysregulated lncRNAs in CHD.We used Gene Expression Omnibus data mining,bioinformatics analysis,and analysis of clinical tissue samples and observed that the novel lncRNA SAP30-2:1 with unknown function was significantly downregulated in damaged cardiac tissues from patients with CHD.Knockdown of lncRNA SAP30-2:1 inhibited the proliferation of human embryonic kidney and AC16 cells and decreased the expression of heart and neural crest derivatives expressed 2(HAND2).Moreover,lncRNA SAP30-2:1 was associated with HAND2 by RNA immunoprecipitation.Overall,these results suggest that lncRNA SAP30-2:1 may be involved in heart development through affecting cell proliferation via targeting HAND2 and may thus represent a novel therapeutic target for CHD.
基金supported by Sichuan Science and Technology Program(No.2022YFS0622)the Science and Technology Development Fund,Macao SAR(Nos.0036/2020/A1 and 0013/2019/A1).
文摘Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology medicines.For numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essential for their biosynthetic and bioenergetic functions.Cancer cells with mutations in isocitrate dehydrogenase 1(IDH1)exhibit differentiation arrest,epigenetic and transcriptional reprogramming,and sensitivity to mitochondrial OXPHOS inhibitors.In this study,we report that berberine,which is widely used in China to treat intestinal infections,acted solely at the mitochondrial electron transport chain(ETC)complex I,and that its association with IDH1 mutant inhibitor(IDH1^(m)i)AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro and in vivo.Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia(AML)patients using combinatory mitochondrial targeted medicines,particularly those who are resistant to or relapsing from IDH1m i.
基金Funding for this project was provided by the Sichuan Science and Technology Program,grant No.2019YJ0696 and the Science and Technology Strategic Cooperation Programs of Luzhou Municipal People’s Government and Southwest Medical University,Grant No.2021LZXNYD-J21 to Xiaoping Lei。
文摘Background After the implementation of the universal two-child policy in China,it was more frequent to have long interpregnancy intervals(IPIs)and advanced maternal age.However,the interactions between long IPIs and advanced maternal age on neonatal outcomes are unknown.Methods The study subjects of this historical cohort study were multiparas with singleton live births between October 1st,2015,and October 31st,2020.IPI was defned as the interval between delivery and conception of the subsequent pregnancy.Logistic regression models were used to calculate adjusted odds ratios(aORs)and 95%confdence intervals(CIs)of the risks of preterm birth(PTB),low birth weight(LBW),small for gestation age,and 1-min Apgar score≤7 in diferent IPI groups.Relative excess risk due to interaction(RERI)was used to evaluate the additive interaction between long IPIs and advanced maternal age.Results Compared with the 24≤IPI≤59 months group,the long IPI group(IPI≥60 months)was associated with a higher risk of PTB(aOR,1.27;95%CI:1.07–1.50),LBW(aOR,1.32;95%CI 1.08–1.61),and one-minute Apgar score≤7(aOR,1.46;95%CI 1.07–1.98).Negative additive interactions(all RERIs<0)existed between long IPIs and advanced maternal age for these neonatal outcomes.Meanwhile,IPI<12 months was also associated with PTB(aOR,1.51;95%CI 1.13–2.01),LBW(aOR,1.50;95%CI 1.09–2.07),and 1-min Apgar score≤7(aOR,1.93;95%CI 1.23–3.04).Conclusions Both short and long IPIs are associated with an increased risk of adverse neonatal outcomes.Appropriate IPI should be recommended to women planning to become pregnant again.In addition,better antenatal care might be taken to balance the inferiority of advanced maternal age and to improve neonatal outcomes.
基金This work was funded by Medical Science and Technology Project of Health Commission of Sichuan Province(No.21PJ091)the Special Project of Science and Technology Research of Sichuan Administration of Traditional Chinese Medicine(2020JC0135)+5 种基金the Applied Basic Research Project of Southwest Medical University(2021ZKQN083)the Doctoral Research Initiation Fund of the Affiliated Hospital of Southwest Medical UniversityThe Basic Research Project of Sichuan Province(No.2019YJ0690)The Major Science and Technology Projects in Sichuan Province(No.2019YFS0531)the University-level Scientific Research Project of Southwest Medical University(2020ZRQNB029)and Natural Science Foundation of Guangxi,China(2020GXNSFAA259021).
文摘As a potential cost-effective feedstock for highly efficient fermentation of glycerol and its downstream product 1,3-propanediol(1,3-PD),duckweed starch was characterized and used for glycerol fermentation,for the first time,in this study.Genes involved in glycerol biosynthesis(gpd1 and gpp2)were overexpressed in Escherichia coli,and genes involved in glycerol catabolism(glpK and gldA)were disrupted,which led to significantly decreased residual sugar levels and dramatically increased glycerol production.The maximum glycerol concentration in fed-batch fermentation reached 102.72 g L^(-1) at 28 h,and the glycerol productivity was 3.67 g L^(-1) h^(-1),which,to our knowledge,is the highest productivity thus far reported.Subsequently,glycerol broth was fermented into 1,3-PD by Klebsiella pneumoniae.The concentration,conversion rate and productivity of 1,3-PD reached 35.54 g L^(-1),40.28%and 0.89 g L^(-1) h^(-1),respectively,without optimization.In summary,the duckweed starch-to-glycerol-to-1,3-PD process is feasible and shows potential for improving glycerol industry competitiveness.
