TY - JOUR

T1 - Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome

AU - Ramond, Francis

AU - Dalgliesh, Caroline

AU - Grimmel, Mona

AU - Wechsberg, Oded

AU - Vetro, Annalisa

AU - Guerrini, Renzo

AU - FitzPatrick, David

AU - Poole, Rebecca L.

AU - Lebrun, Marine

AU - Bayat, Allan

AU - Grasshoff, Ute

AU - Bertrand, Miriam

AU - Witt, Dennis

AU - Turnpenny, Peter D.

AU - Faundes, Víctor

AU - Santa María, Lorena

AU - Mendoza Fuentes, Carolina

AU - Mabe, Paulina

AU - Hussain, Shaun A.

AU - Mullegama, Sureni V.

AU - Torti, Erin

AU - Oehl-Jaschkowitz, Barbara

AU - Salmon, Lina Basel

AU - Orenstein, Naama

AU - Shahar, Noa Ruhrman

AU - Hagari, Ofir

AU - Bazak, Lily

AU - Hoffjan, Sabine

AU - Prada, Carlos E.

AU - Haack, Tobias

AU - Elliott, David J.

N1 - Publisher Copyright: © 2022 The Authors

PY - 2023/4

Y1 - 2023/4

N2 - Purpose: Transformer2 proteins (Tra2α and Tra2β) 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 Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-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 Tra2β-3 isoform. All affected individuals 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 Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-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 Tra2β protein.

AB - Purpose: Transformer2 proteins (Tra2α and Tra2β) 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 Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-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 Tra2β-3 isoform. All affected individuals 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 Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-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 Tra2β protein.

KW - Epilepsy

KW - Infantile spasms

KW - Intellectual disability

KW - Molecular genetics

KW - TRA2B

U2 - 10.1016/j.gim.2022.100003

DO - 10.1016/j.gim.2022.100003

M3 - Journal article

C2 - 36549593

AN - SCOPUS:85147040486

VL - 25

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 4

M1 - 100003

ER -