作者
Ashish R. Deshwar,Cheryl Cytrynbaum,Harsha Murthy,Jessica Zon,David Chitayat,Jonathan Volpatti,Ruth Newbury‐Ecob,Sian Ellard,Hana Lango Allen,Emily Yu,Ramil Noche,Suzi Walker,Stephen W. Scherer,Sonal Mahida,Christopher M. Elitt,Gaël Nicolas,Alice Goldenberg,Pascale Saugier-Véber,François Lecoquierre,Ivana Dabaj,Hannah Meddaugh,Michael Marble,Kim M. Keppler‐Noreuil,Lucy Drayson,Kristin W. Barañano,Anna Chassevent,Katie Agre,Pascaline Létard,Frédéric Bilan,Gwenaël Le Guyader,Annie Laquerrière,Keri Ramsey,Lindsay B. Henderson,Lauren Brady,Mark A. Tarnopolsky,Matthew N. Bainbridge,Jennifer Friedman,Yline Capri,Larissa Athayde,Fernando Kok,Juliana Gurgel‐Giannetti,Gian Paolo Ramelli,Susan Blaser,James J. Dowling,Rosanna Weksberg
摘要
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.