Citations 2
Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications
Deshwar, Ashish R. , Cytrynbaum, Cheryl , Murthy, Harsha, Zon, Jessica, Volpatti, Jonathan, Newbury‐Ecob, Ruth , Yu, Emily, Walker, Suzi, Scherer, Stephen W. , Mahida, Sonal , Elitt, Christopher M. , Nicolas, Gaël , Goldenberg, Alice , Saugier-Véber, Pascale , Lecoquierre, François , Dabaj, Ivana , Meddaugh, Hannah, Marble, Michael , Keppler‐Noreuil, Kim M. , Drayson, Lucy, Barañano, Kristin , Chassevent, Anna , Agre, Katie, Létard, Pascaline , Laquerrière, Annie, Ramsey, Keri , Henderson, Lindsay B. , Brady, Lauren , Tarnopolsky, Mark A. , Bainbridge, Matthew N. , Friedman, Jennifer , Capri, Yline , Athayde, Larissa Sampaio de, Ramos, Luiza , Blaser, Susan , Scherer, Stephen W , Nicolas, Gaël , Dabaj, Ivana , Dowling, James J , Lecoquierre, Francois , Tarnopolsky, Mark , Chitayat, David A. , Ellard, Sian , Allen, Hana Lango , Noche, Ramil R. , Bilan, Frédéric , Guyader, Gwenaël Le , Kok, Fernando , Gurgel‐Giannetti, Juliana , Weksberg, Rosanna
Brain | December 8, 2022 | Volume: 146 | Issue: 6 | Pages: 2285-2297
Abstract The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.
Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy
Helman, Guy , Zarekiani, Parand , Tromp, Samantha A. M., Andrews, Ashley , Bonkowsky, Joshua L. , Chassevent, Anna , Giorgio, Elisa , Pippucci, Tommaso , Wei, Shen, Smith‐Hicks, Constance , Vaula, Giovanna , Schimmel, Mareike , Vollert, Kurt, Shimizu, Fumitaka , Kanda, Takashi , Lynch, Matthew , Roscioli, Tony , Taft, Ryan J. , Simons, Cas , Bugiani, Marianna , Shen, Wei , Bonkowsky, Joshua L , Willemsen, Michèl A A P , Shimizu, Fumitaka , van der Knaap, Marjo S , Shen, Wei , Giorgio, Elisa , Simons, Cas , Botto, Lorenzo D. , Kuijpers, Taco Willem , Knaap, Marjo S. van der
Annals of Neurology | August 10, 2022 | Volume: 92 | Issue: 5 | Pages: 895-901
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