Somatic genetic rescue of a germline ribosome assembly defect
Shengjiang Tan
(1, 2, 3)
,
Laëtitia Kermasson
(4)
,
Christine Hilcenko
(1, 2, 3)
,
Vasileios Kargas
(1, 2, 3)
,
David Traynor
(1, 2, 3)
,
Ahmed Boukerrou
(1, 2, 3)
,
Norberto Escudero-Urquijo
(1, 2, 3)
,
Alexandre Faille
(1, 2, 3)
,
Alexis Bertrand
(4)
,
Maxim Rossmann
(1, 2, 3)
,
Beatriz Goyenechea
(3, 5)
,
Jonathan Moreil
(4)
,
Olivier Alibeu
(4, 6)
,
Blandine Beaupain
(7)
,
Christine Bôle-Feysot
(4, 6)
,
Stefano Fumagalli
(8)
,
Sophie Kaltenbach
(9, 10, 11)
,
Jean-Alain Martignoles
(12)
,
Cécile Masson
(4)
,
Patrick Nitschké
(4)
,
Mélanie Parisot
(4, 6)
,
Aurore Pouliet
(4, 6)
,
Isabelle Radford-Weiss
(9, 10, 11)
,
Frédéric Tores
(4)
,
Jean-Pierre de Villartay
(4)
,
Mohammed Zarhrate
(4, 6)
,
Ai Ling Koh
(13)
,
Kong Boo Phua
(13)
,
Bruno Reversade
(14)
,
Peter Bond
(15, 16)
,
Christine Bellanné-Chantelot
(17)
,
Isabelle Callebaut
(18)
,
François Delhommeau
(12)
,
Jean Donadieu
(7)
,
Alan Warren
(1, 2, 3)
,
Patrick Revy
(4)
1
CIMR -
Cambridge Institute for Medical Research
2 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute
3 CAM - University of Cambridge [UK]
4 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
5 Babraham Research Campus [Cambridge, Royaume-Uni]
6 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
7 CHU Trousseau [APHP]
8 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
9 UPD5 - Université Paris Descartes - Paris 5
10 USPC - Université Sorbonne Paris Cité
11 Hôpital Necker - Enfants Malades [AP-HP]
12 CRSA - Centre de Recherche Saint-Antoine
13 KK Women's and Children's Hospital [Singapore]
14 GIS - Genome Institute of Singapore
15 Bioinformatics Institute [Singapore]
16 NUS - National University of Singapore
17 CHU Pitié-Salpêtrière [AP-HP]
18 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie
2 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute
3 CAM - University of Cambridge [UK]
4 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
5 Babraham Research Campus [Cambridge, Royaume-Uni]
6 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
7 CHU Trousseau [APHP]
8 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
9 UPD5 - Université Paris Descartes - Paris 5
10 USPC - Université Sorbonne Paris Cité
11 Hôpital Necker - Enfants Malades [AP-HP]
12 CRSA - Centre de Recherche Saint-Antoine
13 KK Women's and Children's Hospital [Singapore]
14 GIS - Genome Institute of Singapore
15 Bioinformatics Institute [Singapore]
16 NUS - National University of Singapore
17 CHU Pitié-Salpêtrière [AP-HP]
18 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie
Norberto Escudero-Urquijo
- Fonction : Auteur
- PersonId : 808564
- ORCID : 0000-0002-8201-5884
Mélanie Parisot
- Fonction : Auteur
- PersonId : 778147
- ORCID : 0000-0003-4312-2035
Jean-Pierre de Villartay
- Fonction : Auteur
- PersonId : 756189
- ORCID : 0000-0001-5987-0463
- IdRef : 070707820
Bruno Reversade
- Fonction : Auteur
- PersonId : 758347
- ORCID : 0000-0002-4070-7997
- IdRef : 109134621
Peter Bond
- Fonction : Auteur
- PersonId : 798646
- ORCID : 0000-0003-2900-098X
Christine Bellanné-Chantelot
- Fonction : Auteur
- PersonId : 757816
- ORCID : 0000-0001-8415-6771
- IdRef : 18315438X
Alan Warren
- Fonction : Auteur
- PersonId : 793479
- ORCID : 0000-0001-9277-4553
Patrick Revy
- Fonction : Auteur
- PersonId : 738943
- IdHAL : patrick-revy
- ORCID : 0000-0003-0758-8022
- IdRef : 154700126
Résumé
Abstract Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila . Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.
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Final Version SGR EIF6 Nat comm WO Suppl101520.pdf (4.66 Mo)
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