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 CasagrandaJustyna 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 MacElreavey, Ehud Banne, Naomi Weintrob, Bruria BenZeev, Andrew H. Sinclair

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Article number3403
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

Funding

FundersFunder number
ANR-17-CE14-0038-01ANR-19-CE140022, 739510, ANR-19-CE14-0012
Australian Drosophila Biomedical Research Facility
Medical Research Future Fund Stem Cells MissionMRF1201781
NCRIS-enabled
Novo Nordisk Foundation reNEW Center for Stem Cell MedicineNNF21CC0073729
Stafford Fox Foundation
National Institutes of HealthP40OD018537
Victorian Clinical Genetics Services
Health Science Center, University of North Texas
Australian Research CouncilFT100100764, 1174040
National Health and Medical Research Council1074258, 1156942
Agence Nationale de la RechercheANR-10-LABX-73
State Government of Victoria
Bioplatforms Australia

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