TY - JOUR
T1 - Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
AU - Ayers, Katie L.
AU - Eggers, Stefanie
AU - Rollo, Ben N.
AU - Smith, Katherine R.
AU - Davidson, Nadia M.
AU - Siddall, Nicole A.
AU - Zhao, Liang
AU - Bowles, Josephine
AU - Weiss, Karin
AU - Zanni, Ginevra
AU - Burglen, Lydie
AU - Ben-Shachar, Shay
AU - Rosensaft, Jenny
AU - Raas-Rothschild, Annick
AU - Jørgensen, Anne
AU - Schittenhelm, Ralf B.
AU - Huang, Cheng
AU - Robevska, Gorjana
AU - van den Bergen, Jocelyn
AU - Casagranda, Franca
AU - Cyza, Justyna
AU - Pachernegg, Svenja
AU - Wright, David K.
AU - Bahlo, Melanie
AU - Oshlack, Alicia
AU - O’Brien, Terrence J.
AU - Kwan, Patrick
AU - Koopman, Peter
AU - Hime, Gary R.
AU - Girard, Nadine
AU - Hoffmann, Chen
AU - Shilon, Yuval
AU - Zung, Amnon
AU - Bertini, Enrico
AU - Milh, Mathieu
AU - Ben Rhouma, Bochra
AU - Belguith, Neila
AU - Bashamboo, Anu
AU - MacElreavey, Kenneth
AU - Banne, Ehud
AU - Weintrob, Naomi
AU - BenZeev, Bruria
AU - Sinclair, Andrew H.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85161723390&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39040-0
DO - 10.1038/s41467-023-39040-0
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C2 - 37296101
AN - SCOPUS:85161723390
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3403
ER -