Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Nature Communications Year : 2019

Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

1 I2BC - Institut de Biologie Intégrative de la Cellule
2 Equipe Inserm U1163 - Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia
3 Center for Molecular medicine [Utrecht]
4 Department of Genetics [Utrecht, the Netherlands]
5 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie
6 Service de néphrologie pédiatrique [CHU Necker]
7 ICSN - Institut de Chimie des Substances Naturelles
8 Department of Medicine [Boston, MA, USA]
9 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
10 Service de biochimie métabolique [CHU Necker]
11 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
12 PPN - 3P5 - Plateforme Protéomique Necker [SFR Necker]
13 Equipe Inserm U1163 - Genome dynamics in the immune system
14 Plateforme de génomique [SFR Necker]
15 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
16 U1000 - Neuroimagerie en psychiatrie
17 Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension
18 Unité Néphrologie Pédiatrique [CHRU Lille]
19 Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris]
20 Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL]
21 Service de Pathologie [Hôpital Femme-Mère-Enfant, HCL]
22 UCBL - Université Claude Bernard Lyon 1
23 Department of Medicine - Division of Nephrology [Boston, MA, USA]
24 Pediatric Nephrology Institute [Haifa, Israel]
25 Service de Génétique Médicale [CHU Necker]
Ewen Lescop
Patrick Revy
Mélanie Parisot
  • Function : Author
  • PersonId : 910011
Audrey Laurent
  • Function : Author


N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t6A) is a universal modification essential for translational accuracy and efficiency. The t6A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.


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Dates and versions

inserm-02322309 , version 1 (21-10-2019)



Christelle C. Arrondel, Sophia Missoury, Rozemarijn Snoek, Julie Patat, Giulia Menara, et al.. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. Nature Communications, 2019, 10 (1), pp.3967. ⟨10.1038/s41467-019-11951-x⟩. ⟨inserm-02322309⟩
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