Murdoch Children's Research Institute, The Royal Children's Hospital, Victoria, Australia.
Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
Ann Neurol. 2022 Nov;92(5):895-901. doi: 10.1002/ana.26477. Epub 2022 Aug 20.
NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895-901.
NOTCH1 属于 NOTCH 蛋白家族，可调节细胞命运和炎症反应。体细胞和种系 NOTCH1 变异与癌症、Adams-Oliver 综合征和心血管缺陷有关。我们描述了 7 名无关联患者，他们具有脑白质病变伴钙化和 NOTCH1 中杂合性新获得功能变异。免疫分析显示 CSF IP-10 上调，这是 NOTCH1 信号下游分泌的细胞因子。尸检显示广泛的脑白质病变和伴有血管钙化的微血管病。这些证据表明，NOTCH1 中的杂合性获得性功能变异导致慢性中枢神经系统 (CNS) 炎症反应，从而导致伴有脑白质病变的钙化性微血管病。神经病学年鉴 2022;92:895-901.
