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

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
ISSN2041-1722
DOIs
Publication statusPublished - 9 Jun 2023

Fingerprint

Dive into the research topics of 'Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects'. Together they form a unique fingerprint.

Cite this