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 Casagranda; Justyna 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 McElreavey; Ehud Banne; Naomi Weintrob; Bruria BenZeev; Andrew H. Sinclair

doi:10.1038/s41467-023-39040-0

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 McElreavey, Ehud Banne, Naomi Weintrob, Bruria BenZeev, Andrew H. Sinclair

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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 language	English
Article number	3403
Number of pages	21
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39040-0
Publication status	Published - 9 Jun 2023

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10.1038/s41467-023-39040-0Licence: CC BY

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Ayers, K. L., Eggers, S., Rollo, B. N., Smith, K. R., Davidson, N. M., Siddall, N. A., Zhao, L., Bowles, J., Weiss, K., Zanni, G., Burglen, L., Ben-Shachar, S., Rosensaft, J., Raas-Rothschild, A., Jørgensen, A., Schittenhelm, R. B., Huang, C., Robevska, G., van den Bergen, J., ... Sinclair, A. H. (2023). Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects. Nature Communications, 14(1), Article 3403. https://doi.org/10.1038/s41467-023-39040-0

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title = "Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects",

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.",

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

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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, McElreavey, K, Banne, E, Weintrob, N, BenZeev, B & Sinclair, AH 2023, 'Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects', Nature Communications, vol. 14, no. 1, 3403. https://doi.org/10.1038/s41467-023-39040-0

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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 - McElreavey, Kenneth

AU - Banne, Ehud

AU - Weintrob, Naomi

AU - BenZeev, Bruria

AU - Sinclair, Andrew H.

PY - 2023/6/9

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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.

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

Abstract

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Author Correction: Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects (Nature Communications, (2023), 14, 1, (3403), 10.1038/s41467-023-39040-0)

Discovering new drugs for epilepsy using personalised medicine

Next Generation Imaging Biomarkers for Mild Traumatic Brain Injury

Disorders of Sex Development: Genetics, diagnosis, Informing Clinical Care

Monash Proteomics & Metabolomics Platform (MPMP)

Cite this

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

Abstract

Access to Document

Other files and links

Research output

Author Correction: Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects (Nature Communications, (2023), 14, 1, (3403), 10.1038/s41467-023-39040-0)

Projects

Discovering new drugs for epilepsy using personalised medicine

Next Generation Imaging Biomarkers for Mild Traumatic Brain Injury

Disorders of Sex Development: Genetics, diagnosis, Informing Clinical Care

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Monash Proteomics & Metabolomics Platform (MPMP)

Cite this