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

Francis Ramond, Caroline Dalgliesh, Mona Grimmel, Oded Wechsberg, Annalisa Vetro, Renzo Guerrini, David FitzPatrick, Rebecca L. Poole, Marine Lebrun, Allan Bayat, Ute Grasshoff, Miriam Bertrand, Dennis Witt, Peter D. Turnpenny, Víctor Faundes, Lorena Santa María, Carolina Mendoza Fuentes, Paulina Mabe, Shaun A. Hussain, Sureni V. MullegamaErin Torti, Barbara Oehl-Jaschkowitz, Lina Basel Salmon, Naama Orenstein, Noa Ruhrman Shahar, Ofir Hagari, Lily Bazak, Sabine Hoffjan, Carlos E. Prada, Tobias Haack, David J. Elliott

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish
Article number100003
JournalGenetics in Medicine
Volume25
Issue number4
DOIs
StatePublished - Apr 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Funding

This work was supported by the Biotechnology and Biological Sciences Research Council grants BB/S008039/1 and BB/W002019/1. R.G. is supported by the Tuscany Region Call for Health 2018 (grant DECODE-EE) and the Brain project by Fondazione CA.RI.FI. R.G. and A.V. are members of the European Reference Network for rare and complex epilepsies. V.F. was funded by the Vice-chancellorship for Research and Development of the University of Chile (Project code #0313/2022). We thank all of the individuals and their families for their participation in this study. V.F. and L.S.M. acknowledge Paulina Morales and Angela Peña for their technical support. This work was supported by the Biotechnology and Biological Sciences Research Council grants BB/S008039/1 and BB/W002019/1. R.G. is supported by the Tuscany Region Call for Health 2018 (grant DECODE-EE) and the Brain project by Fondazione CA.RI.FI. R.G. and A.V. are members of the European Reference Network for rare and complex epilepsies. V.F. was funded by the Vice-chancellorship for Research and Development of the University of Chile (Project code #0313/2022). Conceptualization: F.R. C.E.P. D.J.E.; Funding Acquisition: D.J.E.; Investigation: F.R. C.D. M.G. O.W. A.V. R.G. D.F. R.L.P. M.L. A.B. U.G. M.B. D.W. P.D.T. V.F. L.S.M. C.M.F. P.M. S.A.H. S.V.M. E.T. B.O.-J. L.B.S. N.O. N.R.S. O.H. L.B. S.H. C.E.P. T.H. D.J.E.; Supervision: F.R. D.J.E.; Writing - original draft: F.R, V.F. D.J.E.; Writing - review & editing: C.D. M.G. O.W. A.V. R.G. D.F. R.L.P. A.B. P.D.T. S.H. T.H. This study was approved by the Medical Ethics Committee of the Saint-Etienne University Hospital, acting as a central Institutional Review Board. Written informed consent for DNA analysis and the use of medical data for this publication was obtained from parents or legal representatives of the children. All participants and families consented to take part in the study and gave permission to publish photographs when corresponded.

FundersFunder number
Fondazione CA.RI.FI
Saint-Etienne University Hospital
Tuscany Region Call for Health
Vice-chancellorship for Research and Development of the University of Chile0313/2022
Biotechnology and Biological Sciences Research CouncilBB/W002019/1, BB/S008039/1

    Keywords

    • Epilepsy
    • Infantile spasms
    • Intellectual disability
    • Molecular genetics
    • TRA2B

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