Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects

Katie L. Ayers (), Stefanie Eggers, Ben N. Rollo, Katherine R. Smith, Nadia M. Davidson, Nicole A. Siddall, Liang Zhao, Josephine Bowles, Karin Weiss, Ginevra Zanni, Lydie Burglen, Shay Ben-Shachar, Jenny Rosensaft, Annick Raas-Rothschild, Anne Jørgensen, Ralf B. Schittenhelm, Cheng Huang, Gorjana Robevska, Jocelyn van den Bergen, Franca Casagranda, Justyna Cyza, Svenja Pachernegg, David K. Wright, Melanie Bahlo, Alicia Oshlack, Terrence J. O’Brien, Patrick Kwan, Peter Koopman, Gary R. Hime, Nadine Girard, Chen Hoffmann, Yuval Shilon, Amnon Zung, Enrico Bertini, Mathieu Milh, Bochra Ben Rhouma, Neila Belguith, Anu Bashamboo, Kenneth McElreavey, Ehud Banne, Naomi Weintrob, Bruria BenZeev and Andrew H. Sinclair
Additional contact information
Katie L. Ayers: The Murdoch Children’s Research Institute
Stefanie Eggers: The Victorian Clinical Genetics Services
Ben N. Rollo: Monash University, Alfred Centre
Katherine R. Smith: Walter and Eliza Hall Institute of Medical Research
Nadia M. Davidson: Walter and Eliza Hall Institute of Medical Research
Nicole A. Siddall: The University of Melbourne
Liang Zhao: The University of Queensland
Josephine Bowles: The University of Queensland
Karin Weiss: Rappaport Faculty of Medicine, Institute of Technology
Ginevra Zanni: Bambino Gesù Children’s Hospital, IRCCS
Lydie Burglen: APHP. Sorbonne Université, Hôpital Trousseau
Shay Ben-Shachar: Genetic Institute, Tel Aviv Sourasky Medical Center
Jenny Rosensaft: Hebrew University Hadassah Medical School
Annick Raas-Rothschild: Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center
Anne Jørgensen: Copenhagen University Hospital, Rigshospitalet
Ralf B. Schittenhelm: Monash University
Cheng Huang: Monash University
Gorjana Robevska: The Murdoch Children’s Research Institute
Jocelyn van den Bergen: The Murdoch Children’s Research Institute
Franca Casagranda: The University of Melbourne
Justyna Cyza: The Murdoch Children’s Research Institute
Svenja Pachernegg: The Murdoch Children’s Research Institute
David K. Wright: Monash University, Alfred Centre
Melanie Bahlo: Walter and Eliza Hall Institute of Medical Research
Alicia Oshlack: The Peter MacCallum Cancer Centre
Terrence J. O’Brien: Monash University, Alfred Centre
Patrick Kwan: Monash University, Alfred Centre
Peter Koopman: The University of Queensland
Gary R. Hime: The University of Melbourne
Nadine Girard: Aix-Marseille Université, APHM. Department of Pediatric Neurology, Timone Hospital
Chen Hoffmann: Radiology Department, Sheba medical Centre
Yuval Shilon: Hebrew University Hadassah Medical School
Amnon Zung: Kaplan Medical Center
Enrico Bertini: Bambino Gesù Children’s Hospital, IRCCS
Mathieu Milh: Aix-Marseille Université, APHM. Department of Pediatric Neurology, Timone Hospital
Bochra Ben Rhouma: University of Gabes
Neila Belguith: Sfax University
Anu Bashamboo: Institut Pasteur, Université de Paris, CNRS UMR3738, Human Developmental Genetics
Kenneth McElreavey: Institut Pasteur, Université de Paris, CNRS UMR3738, Human Developmental Genetics
Ehud Banne: Hebrew University Hadassah Medical School
Naomi Weintrob: Tel Aviv University
Bruria BenZeev: Sheba Medical Center
Andrew H. Sinclair: The Murdoch Children’s Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Squamous 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,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Date: 2023
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DOI: 10.1038/s41467-023-39040-0

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