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

Ayers, KL; Eggers, S; Rollo, BN; Smith, KR; Davidson, NM; Siddall, NA; Zhao, L; Bowles, J; Weiss, K; Zanni, G; Burglen, L; Ben-Shachar, S; Rosensaft, J; Raas-Rothschild, A; J&#248;rgensen, A; Schittenhelm, RB; Huang, C; Robevska, G; van den Bergen, J; Casagranda, F; Cyza, J; Pachernegg, S; Wright, DK; Bahlo, M; Oshlack, A; O&#39;Brien, TJ; Kwan, P; Koopman, P; Hime, GR; Girard, N; Hoffmann, C; Shilon, Y; Zung, A; Bertini, E; Milh, M; Ben Rhouma, B; Belguith, N; Bashamboo, A; MacElreavey, K; Banne, E; Weintrob, N; BenZeev, B; Sinclair, AH

Author(s): Ayers, KL; Eggers, S; Rollo, BN; Smith, KR; Davidson, NM; Siddall, NA; Zhao, L; Bowles, J; Weiss, K; Zanni, G; Burglen, L; Ben-Shachar, S; Rosensaft, J; Raas-Rothschild, A; Jørgensen, A; Schittenhelm, RB; Huang, C; Robevska, G; van den Bergen, J; Casagranda, F; Cyza, J; Pachernegg, S; Wright, DK; Bahlo, M; Oshlack, A; O'Brien, TJ; Kwan, P; Koopman, P; Hime, GR; Girard, N; Hoffmann, C; Shilon, Y; Zung, A; Bertini, E; Milh, M; Ben Rhouma, B; Belguith, N; Bashamboo, A; MacElreavey, K; Banne, E; Weintrob, N; BenZeev, B; Sinclair, AH;
Details: Publication Year 2023-06-09,Volume 14,Issue #1,Page 3403
Journal Title: Nature Communications
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.
Publisher: NPG
Keywords: Male; Humans; Testis/metabolism; Intellectual Disability; Induced Pluripotent Stem Cells/metabolism; RNA-Binding Proteins/genetics/metabolism; Gonadal Dysgenesis; Antigens, Neoplasm
Research Division(s): Blood Cells And Blood Cancer; Population Health And Immunity
PubMed ID: 37296101
Publisher's Version: https://doi.org/10.1038/s41467-023-39040-0
Open Access at Publisher's Site: https://doi.org/ 10.1038/s41467-023-39040-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-39040-0.pdf - (2.37MB, application/pdf)

Creation Date: 2023-06-30 02:15:55

Last Modified: 2023-06-30 02:24:30