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

Nat Commun. 2019 Sep 3;10(1):3967. doi: 10.1038/s41467-019-11951-x.

Christelle Arrondel ¹, Sophia Missoury ², Rozemarijn Snoek ³ ⁴, Julie Patat ¹, Giulia Menara ¹, Bruno Collinet ² ⁵, Dominique Liger ², Dominique Durand ², Olivier Gribouval ¹, Olivia Boyer ¹ ⁶, Laurine Buscara ¹, Gaëlle Martin ¹, Eduardo Machuca ¹, Fabien Nevo ¹, Ewen Lescop ⁷, Daniela A 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, Marina Charbit ⁶, Stéphane Decramer ¹⁷, Robert Novo ¹⁸, Marie-Alice Macher ¹⁹, Bruno Ranchin ²⁰, Justine Bacchetta ²⁰, Audrey Laurent ²⁰, Sophie Collardeau-Frachon ²¹, Albertien M van Eerde ³ ⁴, Friedhelm Hildebrandt ⁸, Daniella Magen ²², Corinne Antignac ¹ ²³, Herman van Tilbeurgh ²⁴, Géraldine Mollet ²⁵

Affiliations

1 Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
2 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
3 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
4 Center for Molecular Medicine, Utrecht University, Utrecht, The Netherlands.
5 Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, UMR7590 CNRS/Sorbonne-Université, UPMC, Paris, France.
6 Department of Pediatric Nephrology, AP-HP, Necker Hospital, Paris, France.
7 Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
8 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
9 Mass Spectrometry Facility, INSERM UMR1163, Imagine Institute, Paris, France.
10 Service de Biochimie métabolomique et protéomique, Hôpital Necker-Enfants Malades, Paris, France.
11 INSERM UMR-S1124, Université de Paris, Paris, France.
12 Proteomics Platform 3P5-Necker, Université de Paris-Structure Fédérative de Recherche Necker, Inserm US24/CNRS, UMS3633, Paris, France.
13 Inserm UMR1163, Laboratory of Genome Dynamics in the Immune System, Labellisé Ligue contre le Cancer, Université de Paris, Imagine Institute, Paris, France.
14 Genomics Core Facility, Structure Fédérative de Recherche Necker, INSERM U1163 and Inserm US24/CNRS UMS3633, Université de Paris, Paris, France.
15 Bioinformatics Platform, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
16 Department of Pediatric Radiology, and Imagine Institute, INSERM UMR 1163 and INSERM U1000, Université de Paris, Hôpital Necker-Enfants Malades, Paris, France.
17 Department of Pediatric Nephrology-Internal Medicine, Purpan Hospital, Toulouse, France.
18 Pediatric Nephrology Unit, University Hospital of Lille, Lille, France.
19 Department of Pediatric Nephrology, AP-HP, Robert Debre Hospital, Paris, France.
20 Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de référence de maladies rénales rares, Université de Lyon, Bron, France.
21 Department of Pathology, Hospices Civils de Lyon-Hôpital Femme-Mère-Enfant, Claude Bernard Lyon 1 University, Bron, France.
22 Pediatric Nephrology Institute-Rambam Health Care Campus-Technion Faculty of Medicine, Haifa, Israel.
23 Department of Genetics, AP-HP, Necker Hospital, Paris, France.
24 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France. [email protected].
25 Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France. [email protected].

PMID: 31481669 DOI: 10.1038/s41467-019-11951-x

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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