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

Christelle Arrondel, Sophia Missoury, Rozemarijn Snoek, Julie Patat, Giulia Menara, Bruno Collinet, Dominique Liger, Dominique Durand, Olivier Gribouval, Olivia Boyer, Laurine Buscara, Gaëlle Martin, Eduardo Machuca, Fabien Nevo, Ewen Lescop, Daniela A. Braun, Anne-Claire Boschat, Sylvia Sanquer, Ida Chiara Guerrera, Patrick Revy, Mélanie Parisot, Cécile Masson, Nathalie Boddaert, Marina Charbit, Stéphane Decramer, Robert Novo, Marie-Alice Macher, Bruno Ranchin, Justine Bacchetta, Audrey Laurent, Sophie Collardeau-Frachon, Albertien M. Eerde, Friedhelm Hildebrandt, Daniella Magen, Corinne Antignac, Herman Tilbeurgh () and Géraldine Mollet ()
Additional contact information
Christelle Arrondel: Imagine Institute
Sophia Missoury: Université Paris-Saclay
Rozemarijn Snoek: University Medical Center Utrecht
Julie Patat: Imagine Institute
Giulia Menara: Imagine Institute
Bruno Collinet: Université Paris-Saclay
Dominique Liger: Université Paris-Saclay
Dominique Durand: Université Paris-Saclay
Olivier Gribouval: Imagine Institute
Olivia Boyer: Imagine Institute
Laurine Buscara: Imagine Institute
Gaëlle Martin: Imagine Institute
Eduardo Machuca: Imagine Institute
Fabien Nevo: Imagine Institute
Ewen Lescop: Université Paris-Saclay
Daniela A. Braun: Harvard Medical School
Anne-Claire Boschat: INSERM UMR1163, Imagine Institute
Sylvia Sanquer: Hôpital Necker-Enfants Malades
Ida Chiara Guerrera: Université de Paris—Structure Fédérative de Recherche Necker, Inserm US24/CNRS
Patrick Revy: Imagine Institute
Mélanie Parisot: Université de Paris
Cécile Masson: Imagine Institute
Nathalie Boddaert: Hôpital Necker-Enfants Malades
Marina Charbit: Necker Hospital
Stéphane Decramer: Purpan Hospital
Robert Novo: University Hospital of Lille
Marie-Alice Macher: Robert Debre Hospital
Bruno Ranchin: Université de Lyon
Justine Bacchetta: Université de Lyon
Audrey Laurent: Université de Lyon
Sophie Collardeau-Frachon: Claude Bernard Lyon 1 University
Albertien M. Eerde: University Medical Center Utrecht
Friedhelm Hildebrandt: Harvard Medical School
Daniella Magen: Pediatric Nephrology Institute-Rambam Health Care Campus-Technion Faculty of Medicine
Corinne Antignac: Imagine Institute
Herman Tilbeurgh: Université Paris-Saclay
Géraldine Mollet: Imagine Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11951-x

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