Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
Katie Ayers
(1, 2)
,
Stefanie Eggers
(3)
,
Ben Rollo
(4)
,
Katherine Smith
(5)
,
Nadia Davidson
(5, 2)
,
Nicole Siddall
(2)
,
Liang Zhao
(6)
,
Josephine Bowles
(6)
,
Karin Weiss
(7)
,
Ginevra Zanni
(8)
,
Lydie Burglen
(9, 10)
,
Shay Ben-Shachar
(11)
,
Jenny Rosensaft
(12)
,
Annick Raas-Rothschild
(13, 14)
,
Anne Jørgensen
(15)
,
Ralf Schittenhelm
(16)
,
Cheng Huang
(16)
,
Gorjana Robevska
(1)
,
Jocelyn van den Bergen
(1)
,
Franca Casagranda
(2)
,
Justyna Cyza
(1)
,
Svenja Pachernegg
(1, 2)
,
David Wright
(4)
,
Melanie Bahlo
(5)
,
Alicia Oshlack
(17, 2)
,
Terrence O'Brien
(4, 2)
,
Patrick Kwan
(4, 2)
,
Peter Koopman
(6)
,
Gary Hime
(2)
,
Nadine Girard
(18)
,
Chen Hoffmann
(13)
,
Yuval Shilon
(12)
,
Amnon Zung
(19, 12)
,
Enrico Bertini
(8)
,
Mathieu Milh
(18)
,
Bochra Ben Rhouma
(20, 21)
,
Neila Belguith
(21, 22)
,
Anu Bashamboo
(23)
,
Ken Mcelreavey
(23)
,
Ehud Banne
(12, 24)
,
Naomi Weintrob
(14, 11)
,
Bruria Benzeev
(13)
,
Andrew Sinclair
(1, 2)
1
MCRI -
Murdoch Children's Research Institute
2 University of Melbourne
3 Victorian Clinical Genetics Services
4 Monash University [Melbourne]
5 WEHI - The Walter and Eliza Hall Institute of Medical Research
6 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
7 Technion - Israel Institute of Technology [Haifa]
8 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
9 CHU Trousseau [APHP]
10 Equipe Inserm U1163 - Génétique des Troubles du Neurodéveloppement = Developmental Brain Disorders Laboratory
11 Tel Aviv Sourasky Medical Center [Tel Aviv]
12 The Hebrew University Hadassah Medical School
13 Chaim Sheba Medical Center
14 TAU - Tel Aviv University
15 Rigshospitalet [Copenhagen]
16 Monash University [Clayton]
17 Peter Mac Callum Cancer Centre
18 Service de pédiatrie et neurologie pédiatrique
19 Kaplan Medical Center [Rehovot, Israel]
20 Université de Gabès = University of Gabes
21 Université de Sfax - University of Sfax
22 Hôpital Charles Nicolle [Tunis]
23 Génétique du Développement humain - Human developmental genetics
24 Wolfson Medical Center
2 University of Melbourne
3 Victorian Clinical Genetics Services
4 Monash University [Melbourne]
5 WEHI - The Walter and Eliza Hall Institute of Medical Research
6 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
7 Technion - Israel Institute of Technology [Haifa]
8 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
9 CHU Trousseau [APHP]
10 Equipe Inserm U1163 - Génétique des Troubles du Neurodéveloppement = Developmental Brain Disorders Laboratory
11 Tel Aviv Sourasky Medical Center [Tel Aviv]
12 The Hebrew University Hadassah Medical School
13 Chaim Sheba Medical Center
14 TAU - Tel Aviv University
15 Rigshospitalet [Copenhagen]
16 Monash University [Clayton]
17 Peter Mac Callum Cancer Centre
18 Service de pédiatrie et neurologie pédiatrique
19 Kaplan Medical Center [Rehovot, Israel]
20 Université de Gabès = University of Gabes
21 Université de Sfax - University of Sfax
22 Hôpital Charles Nicolle [Tunis]
23 Génétique du Développement humain - Human developmental genetics
24 Wolfson Medical Center
Katie Ayers
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- Fonction : Auteur correspondant
- PersonId : 1267396
- ORCID : 0000-0002-6840-3186
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Nicole Siddall
- Fonction : Auteur
- PersonId : 1267397
- ORCID : 0000-0002-0144-8400
Liang Zhao
- Fonction : Auteur
- PersonId : 1267398
- ORCID : 0000-0002-3489-7421
Josephine Bowles
- Fonction : Auteur
- PersonId : 1267399
- ORCID : 0000-0003-2867-7438
Ginevra Zanni
- Fonction : Auteur
- PersonId : 1267400
- ORCID : 0000-0002-6367-1843
Lydie Burglen
- Fonction : Auteur
- PersonId : 757604
- ORCID : 0000-0002-1119-6809
- IdRef : 074482831
Ralf Schittenhelm
- Fonction : Auteur
- PersonId : 1267401
- ORCID : 0000-0001-8738-1878
Cheng Huang
- Fonction : Auteur
- PersonId : 1267402
- ORCID : 0000-0002-4575-1233
Alicia Oshlack
- Fonction : Auteur
- PersonId : 1267403
- ORCID : 0000-0001-9788-5690
Nadine Girard
- Fonction : Auteur
- PersonId : 1267405
- ORCID : 0000-0001-8639-9275
Mathieu Milh
- Fonction : Auteur
- PersonId : 1267406
- ORCID : 0000-0002-2454-8543
Ken Mcelreavey
- Fonction : Auteur
- PersonId : 735033
- IdHAL : ken-mcelreavey
- ORCID : 0000-0001-6582-1801
- IdRef : 052608131
Andrew Sinclair
- Fonction : Auteur
- PersonId : 1267407
- ORCID : 0000-0003-2741-7992
Résumé
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.
Domaines
Sciences du Vivant [q-bio]| Origine | Publication financée par une institution |
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