Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
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Published:2023-06-09
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Ayers Katie L.ORCID, Eggers Stefanie, Rollo Ben N., Smith Katherine R., Davidson Nadia M., Siddall Nicole A.ORCID, Zhao LiangORCID, Bowles JosephineORCID, Weiss Karin, Zanni GinevraORCID, Burglen LydieORCID, Ben-Shachar Shay, Rosensaft Jenny, Raas-Rothschild Annick, Jørgensen Anne, Schittenhelm Ralf B.ORCID, Huang ChengORCID, Robevska Gorjana, van den Bergen Jocelyn, Casagranda Franca, Cyza Justyna, Pachernegg Svenja, Wright David K., Bahlo Melanie, Oshlack AliciaORCID, O’Brien Terrence J., Kwan Patrick, Koopman Peter, Hime Gary R.ORCID, Girard NadineORCID, Hoffmann Chen, Shilon Yuval, Zung Amnon, Bertini Enrico, Milh MathieuORCID, Ben Rhouma Bochra, Belguith Neila, Bashamboo Anu, McElreavey Kenneth, Banne Ehud, Weintrob Naomi, BenZeev Bruria, Sinclair Andrew H.ORCID
Abstract
AbstractSquamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XYGONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.
Funder
Department of Health | National Health and Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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