B. El-yacoubi, M. Bailly, and V. De-crecy-lagard, Biosynthesis and function of posttranscriptional modifications of transfer RNAs, Annu. Rev. Genet, vol.46, pp.69-95, 2012.

B. El-yacoubi, A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification, EMBO J, vol.30, pp.882-893, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00593551

M. Srinivasan, The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A, EMBO J, vol.30, pp.873-881, 2011.

C. T. Lauhon, Mechanism of N6-threonylcarbamoyladenonsine (t(6)A) biosynthesis: isolation and characterization of the intermediate threonylcarbamoyl-AMP, Biochemistry, vol.51, pp.8950-8963, 2012.

A. Costessi, The human EKC/KEOPS complex is recruited to Cullin2 ubiquitin ligases by the human tumour antigen PRAME, PLoS One, vol.7, p.42822, 2012.

D. Y. Mao, Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine, Mol. Cell, vol.32, pp.259-275, 2008.

L. C. Wan, Proteomic analysis of the human KEOPS complex identifies C14ORF142 as a core subunit homologous to yeast Gon7, Nucleic Acids Res, vol.45, pp.805-817, 2017.

W. Zhang, Crystal structures of the Gon7/Pcc1 and Bud32/Cgi121 complexes provide a model for the complete yeast KEOPS complex, Nucleic Acids Res, vol.43, pp.3358-3372, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01220993

P. C. Thiaville, D. Iwata-reuyl, and V. De-crecy-lagard, Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t(6)A), a universal modification of tRNA, RNA Biol, vol.11, pp.1529-1539, 2014.

J. Ramos and D. Fu, The emerging impact of tRNA modifications in the brain and nervous system, Biochim. Biophys. Acta Gene Regul. Mech, vol.1862, pp.412-428, 2019.

W. H. Galloway and A. P. Mowat, Congenital microcephaly with hiatus hernia and nephrotic syndrome in two sibs, J. Med. Genet, vol.5, pp.319-321, 1968.

D. A. Braun, Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome, J. Clin. Invest, vol.128, pp.4313-4328, 2018.

D. A. Braun, Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly, Nat. Genet, vol.49, pp.1529-1538, 2017.
URL : https://hal.archives-ouvertes.fr/hal-02187752

D. A. Braun, Mutations in WDR4 as a new cause of Galloway-Mowat syndrome, Am. J. Med. Genet. A, vol.176, pp.2460-2465, 2018.

E. Colin, Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome, Am. J. Hum. Genet, vol.95, pp.637-648, 2014.

A. Fujita, Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome, Ann. Neurol, vol.84, pp.814-828, 2018.

R. O. Rosti, Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome, J. Med. Genet, vol.54, pp.399-403, 2017.

J. Vodopiutz, WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease, Hum. Mutat, vol.36, pp.1021-1028, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01790726

C. Parthier, The O-carbamoyltransferase TobZ catalyzes an ancient enzymatic reaction, Angew. Chem. Int. Ed. Engl, vol.51, pp.4046-4052, 2012.

B. El-yacoubi, The universal YrdC/Sua5 family is required for the formation of threonylcarbamoyladenosine in tRNA, Nucleic Acids Res, vol.37, pp.2894-2909, 2009.

E. Kisseleva-romanova, Yeast homolog of a cancer-testis antigen defines a new transcription complex, EMBO J, vol.25, pp.3576-3585, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00133495

M. Downey, A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator, Cell, vol.124, pp.1155-1168, 2006.

A. Hecker, Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex, EMBO J, vol.27, pp.2340-2351, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00357948

Y. Y. Liu, Yeast KEOPS complex regulates telomere length independently of its t(6)A modification function, J. Genet. Genomics, vol.45, pp.247-257, 2018.

M. A. Saleem, A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression, J. Am. Soc. Nephrol, vol.13, pp.630-638, 2002.

P. C. Thiaville, Global translational impacts of the loss of the tRNA modification t(6)A in yeast, Micro Cell, vol.3, pp.29-45, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01412631

T. Bizien, A brief survey of state-of-the-art BioSAXS, Protein Pept. Lett, vol.23, pp.217-231, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01461929

V. A. Blomen, Gene essentiality and synthetic lethality in haploid human cells, Science, vol.350, pp.1092-1096, 2015.

L. C. Wan, Structural and functional characterization of KEOPS dimerization by Pcc1 and its role in t6A biosynthesis, Nucleic Acids Res, vol.44, pp.6971-6980, 2016.

R. Shaheen, Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism, Genome Biol, vol.16, p.210, 2015.

A. Trimouille, Further delineation of the phenotype caused by biallelic variants in the WDR4 gene, Clin. Genet, vol.93, pp.374-377, 2018.

A. Alexandrov, M. R. Martzen, and E. M. Phizicky, Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA, RNA, vol.8, pp.1253-1266, 2002.

N. Leulliot, Structure of the yeast tRNA m7G methylation complex, Structure, vol.16, pp.52-61, 2008.

S. Lin, Mettl1/Wdr4-Mediated m(7)G tRNA methylome is required for normal mRNA translation and embryonic stem cell self-renewal and differentiation, Mol. Cell, vol.71, p.245, 2018.

D. Rojas-benitez, C. Eggers, and A. Glavic, Modulation of the proteostasis machinery to overcome stress caused by diminished levels of t6A-modified tRNAs in Drosophila, Biomolecules, vol.7, 2017.

V. De-crecy-lagard, Matching tRNA modifications in humans to their known and predicted enzymes, Nucleic Acids Res, vol.47, pp.2143-2159, 2019.

M. Uhlen, Proteomics. Tissue-based map of the human proteome, Science, vol.347, p.1260419, 2015.
URL : https://hal.archives-ouvertes.fr/hal-02280776

R. D. Gietz and R. H. Schiestl, High-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method, Nat. Protoc, vol.2, pp.31-34, 2007.

A. Pichard-kostuch, Structure-function analysis of Sua5 protein reveals novel functional motifs required for the biosynthesis of the universal t(6)A tRNA modification, RNA, vol.24, pp.926-938, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02183256

K. Thuring, K. Schmid, P. Keller, and M. Helm, Analysis of RNA modifications by liquid chromatography-tandem mass spectrometry, Methods, vol.107, pp.48-56, 2016.

M. C. Serrano-perez, Endoplasmic reticulum-retained podocin mutants are massively degraded by the proteasome, J. Biol. Chem, vol.293, pp.4122-4133, 2018.

F. Touzot, Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome, Proc. Natl. Acad. Sci. USA, vol.107, pp.10097-10102, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00484901

A. Sali, L. Potterton, F. Yuan, H. Van-vlijmen, and M. Karplus, Evaluation of comparative protein modeling by MODELLER, Proteins, vol.23, pp.318-326, 1995.

W. Kabsch and . Xds, Acta Crystallogr. D Biol. Crystallogr, vol.66, pp.125-132, 2010.

A. J. Mccoy, Phaser crystallographic software, J. Appl. Crystallogr, vol.40, pp.658-674, 2007.

M. D. Winn, Overview of the CCP4 suite and current developments, Acta Crystallogr. D Biol. Crystallogr, vol.67, pp.235-242, 2011.

G. Bricogne, BUSTER version 2.10.3 (Global Phasing Ltd, 2017.

P. Emsley and K. Cowtan, Coot: model-building tools for molecular graphics, Acta Crystallogr. D Biol. Crystallogr, vol.60, pp.2126-2132, 2004.

T. C. Terwilliger, Using prime-and-switch phasing to reduce model bias in molecular replacement, Acta Crystallogr. D Biol. Crystallogr, vol.60, pp.2144-2149, 2004.

G. David and J. Perez, Combined sampler robot and high-performance liquid chromatography: a fully automated system for biological small-angle X-ray scattering experiments at the Synchrotron SOLEIL SWING beamline, J. Appl. Cryst, vol.42, pp.892-900, 2009.

D. Franke, ATSAS 2.8: a comprehensive data analysis suite for smallangle scattering from macromolecular solutions, J. Appl. Crystallogr, vol.50, pp.1212-1225, 2017.

M. V. Petoukhov and D. I. Svergun, Global rigid body modeling of macromolecular complexes against small-angle scattering data, Biophys. J, vol.89, pp.1237-1250, 2005.

G. G. Krivov, M. V. Shapovalov, and R. L. Dunbrack, Improved prediction of protein side-chain conformations with SCWRL4, Proteins, vol.77, pp.778-795, 2009.

D. Svergun, C. Barberato, and M. H. Koch, CRYSOL-a program to evaluate X-ray solution scattering of biological macromolecules from atomic coordinates, J. Appl. Cryst, vol.28, pp.768-773, 1995.

E. Valentini, A. G. Kikhney, G. Previtali, C. M. Jeffries, and D. I. Svergun, SASBDB, a repository for biological small-angle scattering data, Nucleic Acids Res, vol.43, pp.357-363, 2015.

R. S. Author, O. G. , O. B. , E. M. , F. N. et al., Antignac recruited patients and collected detailed clinical information for the study. N.B. provided MRI from control individuals and critically interpreted MRI images from patients, and A.M.v.E. provided and analyzed images of renal histology and electron microscopy

J. P. Arrondel, B. C. , D. L. , G. Martin, E. M. et al., performed cell experiments (co-immunoprecipitation, cycloheximide chase, cell culture), qPCR, and western blot experiments. S.M. performed proteins expression and purifications, cristallogenesis trials, diffraction data collection, 3D structure resolution, SAXS data collection, and analysis. B.C. performed OSGEP/ LAGE3/GON7-his expression and purification, and nucleosides preparation from tRNA samples and YRDC WT and mutant enzymatic assay. D.L. performed yeast complementation studies, expression, and purification of yeast tRNAs. D.D. performed SAXS data collection and analysis. E.L. collected and analyzed NMR experiments. A.-C.B. and S.S. performed HPLC MS/MS t 6 A modification analysis. G. Mollet, G. Martin, and I.C.G. performed proteomic studies in human podocyte cell lines. P.R. performed telomere restriction-fragment assays

G. Mollet, H. V. , C. C. , D. L. , S. M. et al., Antignac conceived and coordinated the study, and wrote the manuscript with the input of

, Laurine Buscara 1 , Gaëlle Martin 1 , Eduardo Machuca 1 , Fabien Nevo 1, Sophie Collardeau-Frachon, vol.6

C. Cnrs and U. Paris-sud, 13 Inserm UMR1163, Laboratory of Genome Dynamics in the Immune System, 14 Genomics Core Facility, Structure Fede?ative de Recherche Necker, INSERM U1163 and Inserm US24/CNRS UMS3633, vol.4