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

Christelle Arrondel 1, 2 Sophia Missoury 1 Rozemarijn Snoek 3, 4 Julie Patat 2 Giulia Menara 2 Bruno Collinet 1, 5 Dominique Liger 1 Dominique Durand 1 Olivier Gribouval 2 Olivia Boyer 6, 2 Laurine Buscara 2 Gaëlle Martin 2 Eduardo Machuca 2 Fabien Nevo 2 Ewen Lescop 7 Daniela Braun 8 Anne-Claire Boschat 9 Sylvia Sanquer 10, 11 Ida Chiara Guerrera 12 Patrick Revy 13 Mélanie Parisot 14 Cécile Masson 15 Nathalie Boddaert 16, 17 Marina Charbit 6 Stéphane Decramer 18 Robert Novo 19 Marie-Alice Macher 20 Bruno Ranchin 21 Justine Bacchetta 21 Audrey Laurent 22 Sophie Collardeau-Frachon 23 Albertien van Eerde 3, 4 Friedhelm Hildebrandt 24 Daniella Magen 25 Corinne Antignac 2, 26 Herman van Tilbeurgh 1, * Geraldine Mollet 2, *
* Corresponding author
12 PPN - 3P5 - Plateforme Protéomique Necker [SFR Necker]
SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
13 Equipe Inserm U1163 - Genome dynamics in the immune system
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
14 Plateforme de génomique [SFR Necker]
SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
Abstract : 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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Christelle 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, Nature Publishing Group, 2019, 10 (1), pp.3967. ⟨10.1038/s41467-019-11951-x⟩. ⟨inserm-02322309⟩

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