Clustered variants in the 5′ coding region of <i>TRA2B</i> cause a distinctive neurodevelopmental syndrome

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dc.contributor.authorRamond, Francis
dc.contributor.authorDalgliesh, Caroline
dc.contributor.authorGrimmel, Mona
dc.contributor.authorWechsberg, Oded
dc.contributor.authorVetro, Annalisa
dc.contributor.authorGuerrini, Renzo
dc.contributor.authorFitzPatrick, David
dc.contributor.authorPoole, Rebecca L.
dc.contributor.authorLebrun, Marine
dc.contributor.authorBayat, Allan
dc.contributor.authorGrasshoff, Ute
dc.contributor.authorBertrand, Miriam
dc.contributor.authorWitt, Dennis
dc.contributor.authorTurnpenny, Peter D.
dc.contributor.authorFaundes, Victor
dc.contributor.authorSanta Maria, Lorena
dc.contributor.authorFuentes, Carolina Mendoza
dc.contributor.authorMabe, Paulina
dc.contributor.authorHussain, Shaun A.
dc.contributor.authorMullegama, Sureni V.
dc.contributor.authorTorti, Erin
dc.contributor.authorOehl-Jaschkowitz, Barbara
dc.contributor.authorSalmon, Lina Basel
dc.contributor.authorOrenstein, Naama
dc.contributor.authorShahar, Noa Ruhrman
dc.contributor.authorHagari, Ofir
dc.contributor.authorBazak, Lily
dc.contributor.authorHoffjan, Sabine
dc.contributor.authorPrada, Carlos E.
dc.contributor.authorHaack, Tobias
dc.contributor.authorElliott, David J.
dc.date.accessioned2025-01-20T20:17:14Z
dc.date.available2025-01-20T20:17:14Z
dc.date.issued2023
dc.description.abstractPurpose: Transformer2 proteins (Tra2a and Tra2(3) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.Methods: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of -function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2(3-1 and Tra2(3-3 isoforms from patient-derived cells were performed. Tra2(31-GFP, Tra2(33-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.Results: All variants clustered in the 5 ' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2(3-3 isoform. All affected in-dividuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2(3-1 isoform, whereas they increased the expression of the Tra2(3-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2(3-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2(3-1.Conclusion: Predicted loss-of-function variants clustered in the 5 ' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2(3 protein.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.gim.2022.100003
dc.identifier.eissn1530-0366
dc.identifier.issn1098-3600
dc.identifier.urihttps://doi.org/10.1016/j.gim.2022.100003
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92384
dc.identifier.wosidWOS:000940678900001
dc.issue.numero4
dc.language.isoen
dc.revistaGenetics in medicine
dc.rightsacceso restringido
dc.subjectEpilepsy
dc.subjectInfantile spasms
dc.subjectIntellectual disability
dc.subjectMolecular genetics
dc.subjectTRA2B
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleClustered variants in the 5′ coding region of <i>TRA2B</i> cause a distinctive neurodevelopmental syndrome
dc.typeartículo
dc.volumen25
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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