Nature Communications (Jun 2023)
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,
- Andrew H. Sinclair
Affiliations
- Katie L. Ayers
- The Murdoch Children’s Research Institute
- Stefanie Eggers
- The Victorian Clinical Genetics Services
- Ben N. Rollo
- Department of Neuroscience, Central Clinical School, 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
- Department of Anatomy and Physiology, The University of Melbourne
- Liang Zhao
- Institute for Molecular Bioscience, The University of Queensland
- Josephine Bowles
- Institute for Molecular Bioscience, The University of Queensland
- Karin Weiss
- Genetics Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Institute of Technology
- Ginevra Zanni
- Unit of Muscular and Neurodegenerative Disorders and Unit of Developmental Neurology, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS
- Lydie Burglen
- Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Et Laboratoire de Neurogénétique Moléculaire, Département de Génétique et Embryologie Médicale, APHP. Sorbonne Université, Hôpital Trousseau
- Shay Ben-Shachar
- Genetic Institute, Tel Aviv Sourasky Medical Center
- Jenny Rosensaft
- Genetics Institute, Kaplan Medical Center, Hebrew University Hadassah Medical School
- Annick Raas-Rothschild
- Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center
- Anne Jørgensen
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet
- Ralf B. Schittenhelm
- Monash Proteomics and Metabolomics Facility, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University
- Cheng Huang
- Monash Proteomics and Metabolomics Facility, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University
- Gorjana Robevska
- The Murdoch Children’s Research Institute
- Jocelyn van den Bergen
- The Murdoch Children’s Research Institute
- Franca Casagranda
- Department of Anatomy and Physiology, The University of Melbourne
- Justyna Cyza
- The Murdoch Children’s Research Institute
- Svenja Pachernegg
- The Murdoch Children’s Research Institute
- David K. Wright
- Department of Neuroscience, Central Clinical School, 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
- Department of Neuroscience, Central Clinical School, Monash University, Alfred Centre
- Patrick Kwan
- Department of Neuroscience, Central Clinical School, Monash University, Alfred Centre
- Peter Koopman
- Institute for Molecular Bioscience, The University of Queensland
- Gary R. Hime
- Department of Anatomy and Physiology, 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
- Kaplan Medical Center, Hebrew University Hadassah Medical School
- Amnon Zung
- Pediatrics Department, Kaplan Medical Center
- Enrico Bertini
- Unit of Muscular and Neurodegenerative Disorders and Unit of Developmental Neurology, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS
- Mathieu Milh
- Aix-Marseille Université, APHM. Department of Pediatric Neurology, Timone Hospital
- Bochra Ben Rhouma
- Higher Institute of Nursing Sciences of Gabes, University of Gabes
- Neila Belguith
- Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, 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
- Genetics Institute, Kaplan Medical Center, Hebrew University Hadassah Medical School
- Naomi Weintrob
- Sackler School of Medicine, Tel Aviv University
- Bruria BenZeev
- Sheba Medical Center
- Andrew H. Sinclair
- The Murdoch Children’s Research Institute
- DOI
- https://doi.org/10.1038/s41467-023-39040-0
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
