目的探讨1例痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作(SPPRS)患儿的遗传学病因。方法选取2022年4月因运动发育落后、智力障碍、肌张力增高于南京医科大学附属儿童医院就诊的1例SPPRS患儿为研究对象。回顾患儿相关的临床资料,对患...目的探讨1例痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作(SPPRS)患儿的遗传学病因。方法选取2022年4月因运动发育落后、智力障碍、肌张力增高于南京医科大学附属儿童医院就诊的1例SPPRS患儿为研究对象。回顾患儿相关的临床资料,对患儿及其父母进行全外显子组测序(WES)。检索单核苷酸多态性数据库(dbSNP)、在线人类孟德尔遗传数据库(OMIM)等对患儿的候选致病性变异进行生物信息学分析。根据美国医学遗传学与基因组学学会(ACMG)相关指南对候选变异进行致病性评级。分别以"HACE1基因""痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作""HACE1 gene""Spastic paraplegia and psychomotor retardation with or without seizures"和"SPPRS"为关键词,对中国知网、万方数据知识服务平台、维普网和PubMed数据库进行检索,时间设定为2000年1月1日至2024年4月7日。通过文献复习,绘制SPPRS患者HACE1蛋白的变异谱。本研究通过了南京医科大学附属儿童医院医学伦理委员会的审查(批准号:202404008-1)。结果本研究患儿主要表现为运动发育落后、智力障碍、肌张力增高。MRI显示大脑胼胝体体后部及压部偏小,双侧侧脑室稍增宽。WES检测提示患儿携带HACE1基因c.535(exon7)_(c).538(exon7)delACAG(p.T179fs*5)和c.1678+2(IVS15)T>C复合杂合变异,分别遗传自其父母。根据ACMG相关指南,上述变异分别被评定为可能致病性(PVS1+PM2_(S)upporting)和致病性(PVS1+PM2_(S)upporting+PM3)。共检索到8篇HACE1基因变异所致SPPRS的报道,连同本研究共涉及24例患者,均存在精神运动发育迟缓,共携带18种HACE1基因的变异。结论HACE1基因c.535(exon7)_(c).538(exon7)delACAG(p.T179fs*5)和c.1678+2(IVS15)T>C复合杂合变异可能是本研究患儿的遗传学病因。上述发现丰富了HACE1基因的变异谱和表型谱,为患儿的临床诊断与遗传咨询提供了依据。展开更多
HACE1,an E3 ubiquitin-protein ligase,is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer.However,its role in glioma remains elusive.Here,we observed increased e...HACE1,an E3 ubiquitin-protein ligase,is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer.However,its role in glioma remains elusive.Here,we observed increased expression of HACE1 in gliomas related to control subjects,and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma(LGG)patients receiving radiotherapy.HACE1 knockdown obviously suppressed malignant behaviors of glioma cells,while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo.Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2(NRF2)by competitively binding to NRF2 with another E3 ligase KEAP1.Besides,HACE1 also promoted internal ribosome entry site(IRES)-mediated mRNA translation of NRF2.These effects did not depend on its E3 ligase activity.Finally,we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2,thereby decreasing the response of glioma cells to radiation.Altogether,our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2,and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.展开更多
文摘目的探讨1例痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作(SPPRS)患儿的遗传学病因。方法选取2022年4月因运动发育落后、智力障碍、肌张力增高于南京医科大学附属儿童医院就诊的1例SPPRS患儿为研究对象。回顾患儿相关的临床资料,对患儿及其父母进行全外显子组测序(WES)。检索单核苷酸多态性数据库(dbSNP)、在线人类孟德尔遗传数据库(OMIM)等对患儿的候选致病性变异进行生物信息学分析。根据美国医学遗传学与基因组学学会(ACMG)相关指南对候选变异进行致病性评级。分别以"HACE1基因""痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作""HACE1 gene""Spastic paraplegia and psychomotor retardation with or without seizures"和"SPPRS"为关键词,对中国知网、万方数据知识服务平台、维普网和PubMed数据库进行检索,时间设定为2000年1月1日至2024年4月7日。通过文献复习,绘制SPPRS患者HACE1蛋白的变异谱。本研究通过了南京医科大学附属儿童医院医学伦理委员会的审查(批准号:202404008-1)。结果本研究患儿主要表现为运动发育落后、智力障碍、肌张力增高。MRI显示大脑胼胝体体后部及压部偏小,双侧侧脑室稍增宽。WES检测提示患儿携带HACE1基因c.535(exon7)_(c).538(exon7)delACAG(p.T179fs*5)和c.1678+2(IVS15)T>C复合杂合变异,分别遗传自其父母。根据ACMG相关指南,上述变异分别被评定为可能致病性(PVS1+PM2_(S)upporting)和致病性(PVS1+PM2_(S)upporting+PM3)。共检索到8篇HACE1基因变异所致SPPRS的报道,连同本研究共涉及24例患者,均存在精神运动发育迟缓,共携带18种HACE1基因的变异。结论HACE1基因c.535(exon7)_(c).538(exon7)delACAG(p.T179fs*5)和c.1678+2(IVS15)T>C复合杂合变异可能是本研究患儿的遗传学病因。上述发现丰富了HACE1基因的变异谱和表型谱,为患儿的临床诊断与遗传咨询提供了依据。
基金This work was supported by the National Natural Science Foundation of China(No.81602437,81672645,and 81770787)the Innovation Talent Promotion Plan in Shaanxi Province(No.2018TD-006).
文摘HACE1,an E3 ubiquitin-protein ligase,is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer.However,its role in glioma remains elusive.Here,we observed increased expression of HACE1 in gliomas related to control subjects,and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma(LGG)patients receiving radiotherapy.HACE1 knockdown obviously suppressed malignant behaviors of glioma cells,while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo.Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2(NRF2)by competitively binding to NRF2 with another E3 ligase KEAP1.Besides,HACE1 also promoted internal ribosome entry site(IRES)-mediated mRNA translation of NRF2.These effects did not depend on its E3 ligase activity.Finally,we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2,thereby decreasing the response of glioma cells to radiation.Altogether,our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2,and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.
