학술논문
Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy.
Document Type
Article
Author
Helman, Guy; Zarekiani, Parand; Tromp, Samantha A.M.; Andrews, Ashley; Botto, Lorenzo D.; Bonkowsky, Joshua L.; Chassevent, Anna; Giorgio, Elisa; Pippucci, Tommaso; Wei, Shen; Smith‐Hicks, Constance; Vaula, Giovanna; Willemsen, Michèl A.A.P; Schimmel, Mareike; Vollert, Kurt; Shimizu, Fumitaka; Kanda, Takashi; Lynch, Matthew; Roscioli, Tony; Taft, Ryan J.
Source
Subject
Language
ISSN
0364-5134
Abstract
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 [ABSTRACT FROM AUTHOR]