Journal Article

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

Siddall, Nicole A., Eggers, Stefanie, Huang, Cheng, Oshlack, Alicia, Bowles, Josephine, Zanni, Ginevra, Casagranda, Franca, McElreavey, Kenneth, Ben-Shachar, Shay, O’Brien, Terrence J., Koopman, Peter, Jørgensen, Anne, Zung, Amnon, Belguith, Neila, Pachernegg, Svenja, Hime, Gary R., Smith, Katherine R., Milh, Mathieu, Schittenhelm, Ralf B., Bashamboo, Anu, Robevska, Gorjana, Rollo, Ben N., Raas-Rothschild, Annick, Wright, David K., Weiss, Karin, Girard, Nadine, Davidson, Nadia M., BenZeev, Bruria, Bertini, Enrico, Hoffmann, Chen, Banne, Ehud, Bahlo, Melanie, Burglen, Lydie, Kwan, Patrick, Sinclair, Andrew H., Cyza, Justyna, Ayers, Katie L., Zhao, Liang, van den Bergen, Jocelyn, Ben Rhouma, Bochra, Shilon, Yuval, Rosensaft, Jenny, Weintrob, Naomi

2023

Overview

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 ( I ntellectual disability, N eurodevelopmental defects and D evelopmental delay with 46,X Y GON adal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition. The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/100 / 13/109 / 13/51 / 13/89 / 14/19 / 38 / 38/23 / 38/39 / 45/100 / 45/88 / 45/91 / 59 / 631/136/1425 / 631/208/2489/144 / 64 / 64/24 / 64/60 / 692/163/2743/1526 / 692/308/2056 / 692/617/375/366 / Anomalies / Antigens / Antigens, Neoplasm / Congenital anomalies / Defects / Gonadal Dysgenesis / Humanities and Social Sciences / Humans / Induced Pluripotent Stem Cells / Induced Pluripotent Stem Cells - metabolism / Intellectual disabilities / Intellectual Disability / Life Sciences / Lymphocytes / Lymphocytes T / Male / multidisciplinary / Pluripotency / Proteins / Ribonucleic acid / RNA / RNA-binding protein / RNA-Binding Proteins / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Signal transduction / Squamous cell carcinoma / Stem cells / Testis / Testis - metabolism