Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage

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dc.authoridSuñer, Damian Heine/0000-0001-9374-1219
dc.authoridPascarella, Rosario/0000-0002-0512-9298
dc.authoridHeine-Suñer, Damian/0000-0001-9374-1219
dc.authoridMarafi, Dana/0000-0003-2233-3423
dc.authoridbayramoğlu, sadık etka/0000-0002-9502-4368
dc.authoridBALDUINI, ALESSANDRA/0000-0003-3145-1245
dc.authoridErrichiello, Edoardo/0000-0001-6346-1988
dc.authorwosidSuñer, Damian Heine/AAW-9664-2020
dc.authorwosidAmengual Cladera, Emilia/JZS-9806-2024
dc.authorwosidPascarella, Rosario/AAL-2639-2021
dc.authorwosidHeine-Suñer, Damian/J-8045-2012
dc.authorwosidMarafi, Dana/AAQ-8427-2021
dc.authorwosidRuiz, María Ángeles Gálvez/AAB-1551-2019
dc.authorwosidBauza, Cristofol Vives/AAS-1869-2021
dc.contributor.authorLecca, Mauro
dc.contributor.authorPehlivan, Davut
dc.contributor.authorSuner, Damia Heine
dc.contributor.authorWeiss, Karin
dc.contributor.authorCoste, Thibault
dc.contributor.authorZweier, Markus
dc.contributor.authorOktay, Yavuz
dc.date.accessioned2024-08-04T20:53:35Z
dc.date.available2024-08-04T20:53:35Z
dc.date.issued2023
dc.departmentİnönü Üniversitesien_US
dc.description.abstractThe blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs*33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous ev-idence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunc-tion due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as tightjunctionopathies.en_US
dc.identifier.doi10.1016/j.ajhg.2023.03.005
dc.identifier.endpage690en_US
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.issue4en_US
dc.identifier.pmid36996813en_US
dc.identifier.scopus2-s2.0-85151814172en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage681en_US
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2023.03.005
dc.identifier.urihttps://hdl.handle.net/11616/101276
dc.identifier.volume110en_US
dc.identifier.wosWOS:000976245600001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofAmerican Journal of Human Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectSubependymal Calcificationen_US
dc.subjectMutationsen_US
dc.subjectBrainen_US
dc.subjectCol4a1en_US
dc.subjectDestructionen_US
dc.subjectFamiliesen_US
dc.subjectSupportsen_US
dc.subjectOnseten_US
dc.titleBi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhageen_US
dc.typeArticleen_US

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