BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor.Both proteins are parts of the interferon(IFN)I signaling pathway and are responsible for antiviral defense and innate immun...BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor.Both proteins are parts of the interferon(IFN)I signaling pathway and are responsible for antiviral defense and innate immune response.IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases.Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome,while DDX58 mutation can cause atypical Singleton-Merten syndrome.AIM To characterize children with pediatric rheumatic diseases(PRD)carrying DDX58 or IFIH1 variants.METHODS Clinical exome sequencing was performed on 92 children with different PRD.IFIH1 and DDX58 variants have been detected in 14 children.IFN-I score has been analyzed and the clinical characteristics of patients have been studied.RESULTS A total of seven patients with systemic lupus erythematosus(SLE)(n=2),myelodysplastic syndrome with SLE features at the onset of the disease(n=1),mixed connective tissue disease(MCTD)(n=1),undifferentiated systemic autoinflammatory disease(uSAID)(n=3)have 5 different variants of the DDX58 gene.A common non-pathogenic variant p.D580E has been found in five children.A rare variant of uncertain significance(VUS)p.N354S was found in one patient with uSAID,a rare likely non-pathogenic variant p.E37K in one patient with uSAID,and a rare likely pathogenic variant p.Cys864fs in a patient with SLE.Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants.Seven patients had six different IFIH1 variants.They were presented with uSAID(n=2),juvenile dermatomyositis(JDM)(n=1),SLElike disease(n=1),Periodic fever with aphthous stomatitis,pharyngitis,and adenitis syndrome(n=1),and systemic onset juvenile idiopathic arthritis(n=1).Three patients have VUS p.E627X,one patient has benign variant p.I923V.Rare VUS p.R595H was detected in the JDM patient.Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID.One patient with uSAID has rare VUS p.T520A.All patients had elevated IFN-I scores.CONCLUSION Rare compound-heterozygous IFIH1 variant(p.L679Ifs*2 and p.V599Ffs*5),heterozygous IFIH1 variant(p.T520A)and heterozygous DDX58 variant(p.Cys864fs)are probably disease causative for uSAID and SLE.The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.展开更多
目的探讨RNA传感器干扰素诱导的解旋酶C结构域蛋白1(interferon-induced helicase C domain protein 1,IFIH1)对人乳头瘤病毒18型(human papillomavirus 18,HPV18)阳性的人宫颈癌细胞HeLa增殖、迁移和侵袭的影响。方法利用GEPIA数据库分...目的探讨RNA传感器干扰素诱导的解旋酶C结构域蛋白1(interferon-induced helicase C domain protein 1,IFIH1)对人乳头瘤病毒18型(human papillomavirus 18,HPV18)阳性的人宫颈癌细胞HeLa增殖、迁移和侵袭的影响。方法利用GEPIA数据库分析IFIH1在正常宫颈组织和宫颈癌组织中的表达。Western blot检测IFIH1在C33A和HeLa细胞中的表达。将HPV18基因组转染到正常上皮细胞HaCaT中,并利用Western blot和实时定量PCR检测IFIH1的表达水平。利用实时无标记动态细胞分析技术和CCK8法检测细胞的增殖能力。划痕愈合实验、Transwell迁移实验和侵袭实验分别检测细胞的迁移能力和侵袭能力。Western blot和免疫荧光实验检测STAT3和磷酸化STAT3的蛋白表达和定位。结果GEPIA数据库分析显示IFIH1在宫颈癌组织中的表达量明显高于正常宫颈组织(P<0.05);相比于C33A细胞,HeLa细胞中IFIH1的表达水平明显增加(P<0.01);与正常HaCaT细胞相比,转染HPV18的HaCaT细胞中IFIH1的表达增加(P<0.01);与阴性对照相比,敲低IFIH1明显抑制HeLa细胞的增殖、迁移和侵袭能力,而过表达IFIH1则促进C33A细胞的增殖、迁移和侵袭(P<0.01);敲低IFIH1后,磷酸化STAT3蛋白的表达减少(P<0.01)。结论IFIHI在被HPV感染的宫颈癌细胞中表达增加,这将促进细胞的增殖、迁移和侵袭能力,可能与激活STAT3有关。展开更多
采集102例15岁以下的1型糖尿病患者（糖尿病组）及127名对照者外周血，提取基因组DNA，对IFIH1（Interferon induced with helicase C domain 1）基因多态rs1990760与rs35744605的单核苷酸多态性（SNPs）进行检测。结果显示，糖尿病组...采集102例15岁以下的1型糖尿病患者（糖尿病组）及127名对照者外周血，提取基因组DNA，对IFIH1（Interferon induced with helicase C domain 1）基因多态rs1990760与rs35744605的单核苷酸多态性（SNPs）进行检测。结果显示，糖尿病组与对照组IFIH1 rs35744605等位基因均为野生型G等位基因。糖尿病组IFIH1 rs1990760 A等位基因频率高于对照组（22.1%对13.0%，P＝0.015），提示IFIH1 rs1990760 A等位基因是天津地区儿童1型糖尿病风险基因。展开更多
目的 探讨乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)自发阴转与干扰素诱导解旋酶C域蛋白1(interferon-induced with helicase C domain 1,IFIH1)基因rs1990760位点多态性及环境因素的交互作用。方法 从第一次调查开始至随...目的 探讨乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)自发阴转与干扰素诱导解旋酶C域蛋白1(interferon-induced with helicase C domain 1,IFIH1)基因rs1990760位点多态性及环境因素的交互作用。方法 从第一次调查开始至随访结束最后1次调查完成,选取了张家港市20个村的48 417人进行健康检查并定期随访,截至2018年共有81例HBsAg自发阴转者,708例HBsAg持续阳性者被纳入本研究。利用TaqMan实时聚合酶链反应进行rs1990760基因分型,运用相乘交互作用分析IFIH1基因与环境的交互作用。结果 IFIH1基因rs1990760的基因型频率分布在自发阴转组和持续阳性组之间的差异无统计学意义(P>0.05),显性模型、相加模型均尚未发现rs1990760多态性与HBsAg自发阴转的关联(显性模型:OR=0.91,95%CI=0.56~1.47;相加模型:OR=0.93,95%CI=0.62~1.40);基因-环境交互作用分析显示,rs1990760位点多态性与饮酒存在相乘交互作用(OR=0.34,95%CI=0.14~0.83,P<0.05),与携带rs1990760CC基因型的饮酒者相比,携带CC基因型的不饮酒者更容易发生HBsAg自发阴转(OR=0.39,95%CI=0.18~0.87,P<0.05)。结论 中国汉族人群IFIH1基因rs1990760位点多态性与饮酒的交互作用影响HBsAg阳性者的自发阴转。展开更多
BACKGROUND IFIH1 is a protein-coding gene.Disorders associated with IFIH1 include Aicardi-Goutières syndrome(AGS)type 7 and Singleton-Merten syndrome type 1.Related pathways include RIG-I/MDA5-mediated induction ...BACKGROUND IFIH1 is a protein-coding gene.Disorders associated with IFIH1 include Aicardi-Goutières syndrome(AGS)type 7 and Singleton-Merten syndrome type 1.Related pathways include RIG-I/MDA5-mediated induction of the interferon(IFN)-α/βpathway and the innate immune system.AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment.In infancy,most patients present with psychomotor retardation,axial hypotonia,spasticity,and brain imaging changes Laboratory assessments showed increased IFN-αactivity with upregulation of IFN signaling and IFN-stimulated gene expression.Some patients develop normally in the early stage,and then have episodic neurological deficits.CASE SUMMARY The 5-year-old girl presented with postpartum height and weight growth retardation,language retardation,brain atrophy,convulsions,and growth hormone deficiency.DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation.Heterozygous mutations in the IFIH1 gene were found.Physical examination at admission found that language development was delayed,the reaction to name calling was average,there was no communication with people,but there was eye contact,no social smile,and no autonomous language.However,the child had rich gesture language and body language,could understand instructions,had bad temper.When she wants to achieve something,she starts crying or shouting.Cardiopulmonary examination showed no obvious abnormality,and abdominal examination was normal.Bilateral muscle strength and muscle tone were symmetrical and slightly decreased.Physiological reflexes exist,but pathological reflexes were not elicited.CONCLUSION We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7,which expanded the mutational spectrum of the IFIH1 gene.展开更多
文摘BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor.Both proteins are parts of the interferon(IFN)I signaling pathway and are responsible for antiviral defense and innate immune response.IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases.Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome,while DDX58 mutation can cause atypical Singleton-Merten syndrome.AIM To characterize children with pediatric rheumatic diseases(PRD)carrying DDX58 or IFIH1 variants.METHODS Clinical exome sequencing was performed on 92 children with different PRD.IFIH1 and DDX58 variants have been detected in 14 children.IFN-I score has been analyzed and the clinical characteristics of patients have been studied.RESULTS A total of seven patients with systemic lupus erythematosus(SLE)(n=2),myelodysplastic syndrome with SLE features at the onset of the disease(n=1),mixed connective tissue disease(MCTD)(n=1),undifferentiated systemic autoinflammatory disease(uSAID)(n=3)have 5 different variants of the DDX58 gene.A common non-pathogenic variant p.D580E has been found in five children.A rare variant of uncertain significance(VUS)p.N354S was found in one patient with uSAID,a rare likely non-pathogenic variant p.E37K in one patient with uSAID,and a rare likely pathogenic variant p.Cys864fs in a patient with SLE.Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants.Seven patients had six different IFIH1 variants.They were presented with uSAID(n=2),juvenile dermatomyositis(JDM)(n=1),SLElike disease(n=1),Periodic fever with aphthous stomatitis,pharyngitis,and adenitis syndrome(n=1),and systemic onset juvenile idiopathic arthritis(n=1).Three patients have VUS p.E627X,one patient has benign variant p.I923V.Rare VUS p.R595H was detected in the JDM patient.Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID.One patient with uSAID has rare VUS p.T520A.All patients had elevated IFN-I scores.CONCLUSION Rare compound-heterozygous IFIH1 variant(p.L679Ifs*2 and p.V599Ffs*5),heterozygous IFIH1 variant(p.T520A)and heterozygous DDX58 variant(p.Cys864fs)are probably disease causative for uSAID and SLE.The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.
文摘目的 探讨乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)自发阴转与干扰素诱导解旋酶C域蛋白1(interferon-induced with helicase C domain 1,IFIH1)基因rs1990760位点多态性及环境因素的交互作用。方法 从第一次调查开始至随访结束最后1次调查完成,选取了张家港市20个村的48 417人进行健康检查并定期随访,截至2018年共有81例HBsAg自发阴转者,708例HBsAg持续阳性者被纳入本研究。利用TaqMan实时聚合酶链反应进行rs1990760基因分型,运用相乘交互作用分析IFIH1基因与环境的交互作用。结果 IFIH1基因rs1990760的基因型频率分布在自发阴转组和持续阳性组之间的差异无统计学意义(P>0.05),显性模型、相加模型均尚未发现rs1990760多态性与HBsAg自发阴转的关联(显性模型:OR=0.91,95%CI=0.56~1.47;相加模型:OR=0.93,95%CI=0.62~1.40);基因-环境交互作用分析显示,rs1990760位点多态性与饮酒存在相乘交互作用(OR=0.34,95%CI=0.14~0.83,P<0.05),与携带rs1990760CC基因型的饮酒者相比,携带CC基因型的不饮酒者更容易发生HBsAg自发阴转(OR=0.39,95%CI=0.18~0.87,P<0.05)。结论 中国汉族人群IFIH1基因rs1990760位点多态性与饮酒的交互作用影响HBsAg阳性者的自发阴转。
文摘BACKGROUND IFIH1 is a protein-coding gene.Disorders associated with IFIH1 include Aicardi-Goutières syndrome(AGS)type 7 and Singleton-Merten syndrome type 1.Related pathways include RIG-I/MDA5-mediated induction of the interferon(IFN)-α/βpathway and the innate immune system.AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment.In infancy,most patients present with psychomotor retardation,axial hypotonia,spasticity,and brain imaging changes Laboratory assessments showed increased IFN-αactivity with upregulation of IFN signaling and IFN-stimulated gene expression.Some patients develop normally in the early stage,and then have episodic neurological deficits.CASE SUMMARY The 5-year-old girl presented with postpartum height and weight growth retardation,language retardation,brain atrophy,convulsions,and growth hormone deficiency.DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation.Heterozygous mutations in the IFIH1 gene were found.Physical examination at admission found that language development was delayed,the reaction to name calling was average,there was no communication with people,but there was eye contact,no social smile,and no autonomous language.However,the child had rich gesture language and body language,could understand instructions,had bad temper.When she wants to achieve something,she starts crying or shouting.Cardiopulmonary examination showed no obvious abnormality,and abdominal examination was normal.Bilateral muscle strength and muscle tone were symmetrical and slightly decreased.Physiological reflexes exist,but pathological reflexes were not elicited.CONCLUSION We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7,which expanded the mutational spectrum of the IFIH1 gene.
