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.
| Original language | English |
|---|---|
| Pages (from-to) | 895-901 |
| Number of pages | 7 |
| Journal | Annals of Neurology |
| Volume | 92 |
| Issue number | 5 |
| Early online date | 10 Aug 2022 |
| DOIs | |
| Publication status | Published - Nov 2022 |
Bibliographical note
Funding Information:The authors thank the patients and their families for participation in this study. We also thank Marjolein Breur and Machiel H. Jansen, research technicians, for their excellent work. We thank Joanna Crawford at the University of Queensland Institute for Molecular Bioscience for her efforts on the genome sequencing in patient 1. We thank Edoardo Della Sala and Paola Di Martino, PhD students at the Department of Medical Sciences, University of Torino, Italy, for their contributions to the laboratory work for patient 3. For the evaluation and diagnosis of patient 6, we thank Rong Mao and Pinar Bayrak‐Toydemir from ARUP Laboratories and the University of Utah; and Dr Steven Bleyl, Dr James Bale, Dr Matt Velinder, Dr Steven Boyden, Dr Joseph Yost, Dr Charles Murtaugh, Dr John C. Carey, and Ms Abbey Bentley, all at the University of Utah for their help in the clinical, molecular, and bioinformatic evaluation. G.H. was supported by the Ochsner MD‐PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. P.Z. and M.B. are supported by the ZonMw VENI grant number 016.196.107.
Funding Information:
The authors thank the patients and their families for participation in this study. We also thank Marjolein Breur and Machiel H. Jansen, research technicians, for their excellent work. We thank Joanna Crawford at the University of Queensland Institute for Molecular Bioscience for her efforts on the genome sequencing in patient 1. We thank Edoardo Della Sala and Paola Di Martino, PhD students at the Department of Medical Sciences, University of Torino, Italy, for their contributions to the laboratory work for patient 3. For the evaluation and diagnosis of patient 6, we thank Rong Mao and Pinar Bayrak-Toydemir from ARUP Laboratories and the University of Utah; and Dr Steven Bleyl, Dr James Bale, Dr Matt Velinder, Dr Steven Boyden, Dr Joseph Yost, Dr Charles Murtaugh, Dr John C. Carey, and Ms Abbey Bentley, all at the University of Utah for their help in the clinical, molecular, and bioinformatic evaluation. G.H. was supported by the Ochsner MD-PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. P.Z. and M.B. are supported by the ZonMw VENI grant number 016.196.107.
Publisher Copyright:
© 2022 American Neurological Association.
Funding
The authors thank the patients and their families for participation in this study. We also thank Marjolein Breur and Machiel H. Jansen, research technicians, for their excellent work. We thank Joanna Crawford at the University of Queensland Institute for Molecular Bioscience for her efforts on the genome sequencing in patient 1. We thank Edoardo Della Sala and Paola Di Martino, PhD students at the Department of Medical Sciences, University of Torino, Italy, for their contributions to the laboratory work for patient 3. For the evaluation and diagnosis of patient 6, we thank Rong Mao and Pinar Bayrak‐Toydemir from ARUP Laboratories and the University of Utah; and Dr Steven Bleyl, Dr James Bale, Dr Matt Velinder, Dr Steven Boyden, Dr Joseph Yost, Dr Charles Murtaugh, Dr John C. Carey, and Ms Abbey Bentley, all at the University of Utah for their help in the clinical, molecular, and bioinformatic evaluation. G.H. was supported by the Ochsner MD‐PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. P.Z. and M.B. are supported by the ZonMw VENI grant number 016.196.107. The authors thank the patients and their families for participation in this study. We also thank Marjolein Breur and Machiel H. Jansen, research technicians, for their excellent work. We thank Joanna Crawford at the University of Queensland Institute for Molecular Bioscience for her efforts on the genome sequencing in patient 1. We thank Edoardo Della Sala and Paola Di Martino, PhD students at the Department of Medical Sciences, University of Torino, Italy, for their contributions to the laboratory work for patient 3. For the evaluation and diagnosis of patient 6, we thank Rong Mao and Pinar Bayrak-Toydemir from ARUP Laboratories and the University of Utah; and Dr Steven Bleyl, Dr James Bale, Dr Matt Velinder, Dr Steven Boyden, Dr Joseph Yost, Dr Charles Murtaugh, Dr John C. Carey, and Ms Abbey Bentley, all at the University of Utah for their help in the clinical, molecular, and bioinformatic evaluation. G.H. was supported by the Ochsner MD-PhD Scholarship. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278) and the Medical Research Future Fund (ARG76368). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. P.Z. and M.B. are supported by the ZonMw VENI grant number 016.196.107.
| Funders | Funder number |
|---|---|
| Medical Research Future Fund | ARG76368 |
| ZonMw Veni | 016.196.107 |
| University of Utah | |
| ARUP Laboratories | |
| National Health and Medical Research Council | 1068278 |
| National Health and Medical Research Council | |
| State Government of Victoria | |
| Institute for Molecular Bioscience, University Of Queensland |
