STXBP1 encephalopathy(STXBP1-E)is a rare neurodevelopmental disorder that includes epilepsy;it is caused by de novo STXBP1 mutations.In clinical settings,pharmaceutical interventions to treat STXBP1-E predominantly co...STXBP1 encephalopathy(STXBP1-E)is a rare neurodevelopmental disorder that includes epilepsy;it is caused by de novo STXBP1 mutations.In clinical settings,pharmaceutical interventions to treat STXBP1-E predominantly concentrate on seizure control.However,effective treatments for seizure recurrence,treatment resistance,and common comorbidities remain scarce.Patients with STXBP1-E display a wide range of pathogenic variations that manifest as loss-of-function,gain-of-function,or dominant-negative effects.However,recent studies have primarily investigated the pathogenic mechanisms resulting from loss-of-function mutations using STXBP1 haploinsufficiency models.This approach fails to accurately assess the impact of disease-causing mutations.Moreover,to evaluate new syntaxin-binding protein 1(STXBP1)-targeting drugs,novel models that incorporate disease-causing mutations or even the genetic backgrounds of patients are needed.Here,we discuss the clinical symptoms of STXBP1-E and the relationship between this disorder and STXBP1 mutations.We also review recent progress toward understanding the biological function of STXBP1 and its deficiency-induced cellular defects.We then discuss recent discoveries concerning the pathogenesis of STXBP1-E and the limitations and challenges associated with the current research model.Additionally,we underscore the value of leveraging stem cell technology to study the pathogenic mechanisms of STXBP1-E,and review stem cell transplantation as a potential approach for treating this disorder.We also discuss potential future research directions that need to be resolved.展开更多
癫痫性脑病是婴儿期和儿童早期严重的脑部疾患,其中70%癫痫性脑病与遗传因素相关。突触融合蛋白结合蛋白-1(Syntaxin-binding protein 1,STXBP1)基因编码STXBP1,其发生突变可影响突触囊泡融合及神经递质释放,是引起癫痫性脑病的常见致...癫痫性脑病是婴儿期和儿童早期严重的脑部疾患,其中70%癫痫性脑病与遗传因素相关。突触融合蛋白结合蛋白-1(Syntaxin-binding protein 1,STXBP1)基因编码STXBP1,其发生突变可影响突触囊泡融合及神经递质释放,是引起癫痫性脑病的常见致病基因。STXBP1基因突变的致病机制是单倍剂量不足,STXBP1的补充或激活可能是一种潜在的精准治疗策略。文章对近年来报道的STXBP1基因相关脑病的临床表型、基因研究等进展进行综述。展开更多
基金funded by the Natural Science Foundation of Sichuan Province,grant number 2022NSFSC0607.
文摘STXBP1 encephalopathy(STXBP1-E)is a rare neurodevelopmental disorder that includes epilepsy;it is caused by de novo STXBP1 mutations.In clinical settings,pharmaceutical interventions to treat STXBP1-E predominantly concentrate on seizure control.However,effective treatments for seizure recurrence,treatment resistance,and common comorbidities remain scarce.Patients with STXBP1-E display a wide range of pathogenic variations that manifest as loss-of-function,gain-of-function,or dominant-negative effects.However,recent studies have primarily investigated the pathogenic mechanisms resulting from loss-of-function mutations using STXBP1 haploinsufficiency models.This approach fails to accurately assess the impact of disease-causing mutations.Moreover,to evaluate new syntaxin-binding protein 1(STXBP1)-targeting drugs,novel models that incorporate disease-causing mutations or even the genetic backgrounds of patients are needed.Here,we discuss the clinical symptoms of STXBP1-E and the relationship between this disorder and STXBP1 mutations.We also review recent progress toward understanding the biological function of STXBP1 and its deficiency-induced cellular defects.We then discuss recent discoveries concerning the pathogenesis of STXBP1-E and the limitations and challenges associated with the current research model.Additionally,we underscore the value of leveraging stem cell technology to study the pathogenic mechanisms of STXBP1-E,and review stem cell transplantation as a potential approach for treating this disorder.We also discuss potential future research directions that need to be resolved.
文摘癫痫性脑病是婴儿期和儿童早期严重的脑部疾患,其中70%癫痫性脑病与遗传因素相关。突触融合蛋白结合蛋白-1(Syntaxin-binding protein 1,STXBP1)基因编码STXBP1,其发生突变可影响突触囊泡融合及神经递质释放,是引起癫痫性脑病的常见致病基因。STXBP1基因突变的致病机制是单倍剂量不足,STXBP1的补充或激活可能是一种潜在的精准治疗策略。文章对近年来报道的STXBP1基因相关脑病的临床表型、基因研究等进展进行综述。
