Letter | Published:

Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Nature Genetics volume 49, pages 15291538 (2017) | Download Citation


Galloway–Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR–Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

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  1. 1.

    et al. WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease. Hum. Mutat. 36, 1021–1028 (2015).

  2. 2.

    et al. Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73. Brain 138, 2173–2190 (2015).

  3. 3.

    et al. Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome. Am. J. Hum. Genet. 95, 637–648 (2014).

  4. 4.

    et al. A systematic approach to mapping recessive disease genes in individuals from outbred populations. PLoS Genet. 5, e1000353 (2009).

  5. 5.

    et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150, 533–548 (2012).

  6. 6.

    et al. Proteomic analysis of the human KEOPS complex identifies C14ORF142 as a core subunit homologous to yeast Gon7. Nucleic Acids Res. 45, 805–817 (2017).

  7. 7.

    et al. Gcn4 misregulation reveals a direct role for the evolutionary conserved EKC/KEOPS in the t6A modification of tRNAs. Nucleic Acids Res. 39, 6148–6160 (2011).

  8. 8.

    et al. A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification. EMBO J. 30, 882–893 (2011).

  9. 9.

    et al. The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A. EMBO J. 30, 873–881 (2011).

  10. 10.

    et al. Accurate translation of the genetic code depends on tRNA modified nucleosides. J. Biol. Chem. 277, 16391–16395 (2002).

  11. 11.

    et al. A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator. Cell 124, 1155–1168 (2006).

  12. 12.

    et al. Qri7/OSGEPL, the mitochondrial version of the universal Kae1/YgjD protein, is essential for mitochondrial genome maintenance. Nucleic Acids Res. 37, 5343–5352 (2009).

  13. 13.

    et al. Yeast homolog of a cancer-testis antigen defines a new transcription complex. EMBO J. 25, 3576–3585 (2006).

  14. 14.

    et al. The universal Kae1 protein and the associated Bud32 kinase (PRPK), a mysterious protein couple probably essential for genome maintenance in Archaea and Eukarya. Biochem. Soc. Trans. 37, 29–35 (2009).

  15. 15.

    et al. A chemosensitization screen identifies TP53RK, a kinase that restrains apoptosis after mitotic stress. Cancer Res. 70, 6325–6335 (2010).

  16. 16.

    et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1279–1289 (2015).

  17. 17.

    et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum. Genet. 132, 865–884 (2013).

  18. 18.

    & Specific podocin mutations determine age of onset of nephrotic syndrome all the way into adult life. Kidney Int. 75, 669–671 (2009).

  19. 19.

    et al. tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur. J. Hum. Genet. 25, 545–551 (2017).

  20. 20.

    et al. Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine. Mol. Cell 32, 259–275 (2008).

  21. 21.

    et al. Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex. EMBO J. 27, 2340–2351 (2008).

  22. 22.

    et al. Crystal structures of the Gon7/Pcc1 and Bud32/Cgi121 complexes provide a model for the complete yeast KEOPS complex. Nucleic Acids Res. 43, 3358–3372 (2015).

  23. 23.

    et al. Global translational impacts of the loss of the tRNA modification t6A in yeast. Microb. Cell 3, 29–45 (2016).

  24. 24.

    & Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161, 1606–1618 (2015).

  25. 25.

    et al. A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev. Cell 35, 553–567 (2015).

  26. 26.

    & Divergent roles of IRE1alpha and PERK in the unfolded protein response. Curr. Mol. Med. 6, 5–36 (2006).

  27. 27.

    & The role of the DNA damage response pathways in brain development and microcephaly: insight from human disorders. DNA Repair (Amst.) 7, 1039–1050 (2008).

  28. 28.

    et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat. Genet. 40, 232–236 (2008).

  29. 29.

    et al. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nat. Commun. 6, 8829 (2015).

  30. 30.

    , , , & A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat. Genet. 33, 497–501 (2003).

  31. 31.

    et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J. Am. Soc. Nephrol. 16, 2941–2952 (2005).

  32. 32.

    et al. The human EKC/KEOPS complex is recruited to Cullin2 ubiquitin ligases by the human tumour antigen PRAME. PLoS One 7, e42822 (2012).

  33. 33.

    , & A high-throughput approach for measuring temporal changes in the interactome. Nat. Methods 9, 907–909 (2012).

  34. 34.

    et al. The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J. Cell Biol. 197, 239–251 (2012).

  35. 35.

    , , , & Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17, 428–437 (2007).

  36. 36.

    et al. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J. Clin. Invest. 123, 3243–3253 (2013).

  37. 37.

    et al. KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. J. Clin. Invest. 125, 2375–2384 (2015).

  38. 38.

    et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J. Clin. Invest. 123, 5179–5189 (2013).

  39. 39.

    et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

  40. 40.

    , , & HomozygosityMapper: an interactive approach to homozygosity mapping. Nucleic Acids Res. 37, W593–W599 (2009).

  41. 41.

    et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014).

  42. 42.

    et al. High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing. J. Med. Genet. 49, 756–767 (2012).

  43. 43.

    , , , & CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing. Nucleic Acids Res. 42, W401–W407 (2014).

  44. 44.

    et al. Efficient mutagenesis by Cas9 protein-mediated oligonucleotide insertion and large-scale assessment of single-guide RNAs. PLoS One 9, e98186 (2014).

  45. 45.

    , , , & Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat. Biotechnol. 32, 279–284 (2014).

  46. 46.

    , , & Method for isolation of PCR-ready genomic DNA from zebrafish tissues. Biotechniques 43, 610–614 (2007).

  47. 47.

    , & Comparison of T7E1 and surveyor mismatch cleavage assays to detect mutations triggered by engineered nucleases. G3 (Bethesda) 5, 407–415 (2015).

  48. 48.

    , , & Easy quantitative assessment of genome editing by sequence trace decomposition. Nucleic Acids Res. 42, e168 (2014).

  49. 49.

    , , , & The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 10, 845–858 (2015).

  50. 50.

    et al. Sensitivity of mass spectrometry analysis depends on the shape of the filtration unit used for filter aided sample preparation (FASP). Proteomics 16, 1852–1857 (2016).

  51. 51.

    & MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).

  52. 52.

    et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).

  53. 53.

    et al. A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J. Am. Soc. Nephrol. 13, 630–638 (2002).

  54. 54.

    , , & Analysis of RNA modifications by liquid chromatography-tandem mass spectrometry. Methods 107, 48–56 (2016).

  55. 55.

    et al. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc. Natl. Acad. Sci. USA 107, 10097–10102 (2010).

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We are grateful to the families and participating individuals for their contribution. We thank the Yale Center for Mendelian Genomics (U54HG006504) and the Care4Rare Canada Consortium for WES. We acknowledge D. Ogino (Yamagata University) for providing the nephrology data for patient B60, H. Sartelet (Département de Pathologie, CHU-Sainte-Justine, Université de Montréal) for providing pathology pictures from the renal biopsy from patient B80, S. Blaser (Hospital for Sick Children, Department of Pediatrics, Division of Neuroradiology, University of Toronto) for providing cranial imaging for patient DC, and S. Ameli (Children's Medical Center, Tehran University of Medical Sciences) for providing DNA samples of family B50. We thank A. Reis and A. Ekici (Institute of Human Genetics, University of Erlangen-Nuremberg) for supporting the initial GAMOS mapping study conducted by M.Z. We thank D. Libri (Institut Jacques Monod) and M. Saleem (University of Bristol) for reagents. This research was supported by funding from the National Institutes of Health (DK076683) and the Howard Hughes Medical Institute to F.H. F.H. was also supported as the William E. Harmon Professor. W.T. was supported by the ASN Foundation for Kidney Research. B. Behnam was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (Common Fund). N.D.R., S.V. and B. Callewaert were supported as a research fellow, a postdoctoral research fellow, and a senior clinical investigator, respectively, of the Fund for Scientific Research, Flanders. E.W. was supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). H.Y.G. was supported by the National Research Foundation of Korea, Ministry of Science, ICT and Future planning (2015R1D1A1A01056685) and by the Yonsei University College of Medicine (2015-32-0047). M.T.F.W. was supported by K08-DK095994-05 (NIH) and the Children′s Clinical Research Advisory Committee (CCRAC), Children′s Medical Center, Dallas. M.B. was supported by a Senior Research Scholar Award from Fonds de la Recherche du Québec-Santé (FRQS) and a grant from the Canadian Institutes for Health Research (MOP-84470). O.S.-F. was supported by a KRESCENT Post-Doctoral Fellowship and a McGill Integrated Cancer Research Training (MICRTP) fellowship. T.J.-S. was supported by grant Jo 1324/1-1 from the Deutsche Forschungsgemeinschaft (DFG). T.H. was supported by the German Research Foundation, DFG fellowship (HE 7456/1-1). C.A. was supported by grants from the Agence Nationale de la Recherche (GenPod project ANR-12- BSV1-0033.01), the European Union's Seventh Framework Programme (FP7/2007-2013/no 305608- EURenOmics), the Fondation Recherche Médicale (DEQ20150331682) and the 'Investissements d'avenir' program (ANR-10-IAHU-01). M.F. was supported by grants from the Spanish Society of Nephrology and the Catalan Society of Nephrology. M.D.S. acknowledges financial support from the Department of Health by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423). Work in the laboratory of P.C.D. was supported by the Singapore National Research Foundation under the Singapore–MIT Alliance for Research and Technology, the National Institute of Environmental Health Science (ES017010, ES022858, ES002109) and the National Science Foundation (MCB-1412379). F.O. was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) (EURenOmics; grant 2012-305608). The Nephrogenetics Laboratory at Hacettepe University was established by the Hacettepe University Infrastructure Project (grant 06A101008). P.M.G. was supported by a COBRE Grant (P30 GM110766). C.A.H. was supported by the Dutch Kidney Foundation. S.A.L. was supported by the Max Planck Society and the European Research Council (ERC-2012-StG 310489-tRNAmodi). A. Poduri was supported by the Boston Children's Hospital Translational Research Program.

Author information

Author notes

    • Daniela A Braun
    • , Jia Rao
    •  & Geraldine Mollet

    These authors contributed equally to this work.


  1. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Daniela A Braun
    • , Jia Rao
    • , David Schapiro
    • , Weizhen Tan
    • , Tilman Jobst-Schwan
    • , Johanna Magdalena Schmidt
    • , Jennifer A Lawson
    • , Shazia Ashraf
    • , Charlotte A Hoogstraten
    • , Svjetlana Lovric
    • , Merlin Airik
    • , Tobias Hermle
    • , Shirlee Shril
    • , Eugen Widmeier
    • , Heon Yung Gee
    • , Won-Il Choi
    • , Carolin E Sadowski
    • , Werner L Pabst
    • , Jillian K Warejko
    • , Ankana Daga
    •  & Friedhelm Hildebrandt
  2. Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Imagine Institute, Paris, France.

    • Geraldine Mollet
    • , Olivier Gribouval
    • , Olivia Boyer
    • , Gaëlle Martin
    • , Monica Furlano
    •  & Corinne Antignac
  3. Université Paris Descartes–Sorbonne Paris Cité, Imagine Institute, Paris, France.

    • Geraldine Mollet
    • , Olivier Gribouval
    • , Olivia Boyer
    • , Patrick Revy
    • , Nathalie Boddaert
    • , Gaëlle Martin
    • , Monica Furlano
    •  & Corinne Antignac
  4. Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.

    • Marie-Claire Daugeron
    • , Bruno Collinet
    • , Dominique Liger
    • , Tamara Basta
    •  & Herman van Tilbeurgh
  5. Department of Pediatric Nephrology, Necker Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France.

    • Olivia Boyer
  6. INSERM, U1163, Imagine Institute, Laboratory of Genome Dynamics in the Immune system, Paris, France.

    • Patrick Revy
  7. Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

    • Denny Schanze
    •  & Martin Zenker
  8. Epilepsy Genetics Program and F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Jeremy F P Ullmann
    • , Gessica Truglio
    •  & Annapurna Poduri
  9. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.

    • Jeremy F P Ullmann
    •  & Annapurna Poduri
  10. INSERM, U1163, Imagine Institute, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, and INSERM U1000, Paris, France.

    • Nathalie Boddaert
  11. Department of Pediatric Radiology, Necker Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France.

    • Nathalie Boddaert
  12. Sorbonne Universités UPMC, UFR 927, Sciences de la Vie, Paris, France.

    • Bruno Collinet
  13. Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie UMR 7590, Sorbonne Universités, UPMC, Université Paris 06, Paris, France.

    • Bruno Collinet
  14. Nephrology Department, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma de Barcelona and REDINREN, Barcelona, Spain.

    • Monica Furlano
  15. Proteomics platform 3P5-Necker, Université Paris Descartes–Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France.

    • I Chiara Guerrera
  16. Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

    • Oraly Sanchez-Ferras
    •  & Maxime Bouchard
  17. Departments of Chemistry and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jennifer F Hu
  18. Mass Spectrometry Platform, Imagine Institute, Paris, France.

    • Anne-Claire Boschat
  19. Department of Metabolomic and Proteomic Biochemistry, Necker Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France.

    • Sylvia Sanquer
  20. INSERM UMR-S1124, Paris Descartes–Sorbonne Paris Cité University, Paris, France.

    • Sylvia Sanquer
  21. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

    • Björn Menten
    • , Sarah Vergult
    • , Nina De Rocker
    •  & Bert Callewaert
  22. Department of Medicine, Renal Division, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

    • Eugen Widmeier
  23. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.

    • Heon Yung Gee
  24. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

    • Verena Matejas
  25. Max Planck Institute for Molecular Biomedicine, Muenster, Germany.

    • Karin Scharmann
    • , Sandra D Kienast
    •  & Sebastian A Leidel
  26. Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany.

    • Karin Scharmann
    • , Sandra D Kienast
    •  & Sebastian A Leidel
  27. Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences (IUMS), Tehran, Iran.

    • Babak Behnam
  28. Medical Genetics Branch, National Human Genome Research Institute (NHGRI), Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.

    • Babak Behnam
  29. Department of Diagnostic Imaging, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.

    • Brendan Beeson
    •  & Malcolm Bruce
  30. GeneDx, Gaithersburg, Maryland, USA.

    • Amber Begtrup
    • , Megan T Cho
    •  & Rhonda E Schnur
  31. Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.

    • Gaik-Siew Ch'ng
  32. Department of Pediatric Genetics, MacKay Children's Hospital, Taipei, Taiwan.

    • Shuan-Pei Lin
  33. Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.

    • Shuan-Pei Lin
    •  & Jeng-Daw Tsai
  34. Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.

    • Jui-Hsing Chang
    • , Chyong-Hsin Hsu
    •  & Jeng-Daw Tsai
  35. Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Chao-Huei Chen
    •  & Yu-Yuan Ke
  36. Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Patrick M Gaffney
  37. Internal Medicine and Pediatrics Divisions of Adult and Pediatric Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

    • Patrick E Gipson
  38. Pediatric Nephrology Center of Excellence and Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jameela A Kari
  39. Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia.

    • Cathy Kiraly-Borri
  40. Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.

    • Wai-ming Lai
  41. Service de Génétique Médicale, Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

    • Emmanuelle Lemyre
  42. Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas, USA.

    • Rebecca Okashah Littlejohn
    •  & Elizabeth R Roeder
  43. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Rebecca Okashah Littlejohn
    •  & Elizabeth R Roeder
  44. Department of Pediatrics, Division of Child Neurology, Faculty of Medicine, University of Jordan, Amman, Jordan.

    • Amira Masri
  45. Chronic Kidney Disease Research Center, Tehran University of Medical Science, Tehran, Iran.

    • Mastaneh Moghtaderi
  46. Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

    • Kazuyuki Nakamura
    •  & Takashi Shiihara
  47. Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Hacettepe University, Ankara, Turkey.

    • Fatih Ozaltin
    •  & Rezan Topaloglu
  48. Nephrogenetics Laboratory, Hacettepe University Faculty of Medicine, Hacettepe University, Ankara, Turkey.

    • Fatih Ozaltin
  49. Hacettepe University Center for Biobanking and Genomics, Hacettepe University, Ankara, Turkey.

    • Fatih Ozaltin
  50. Department of Pathology, Ghent University Hospital, Ghent, Belgium.

    • Marleen Praet
  51. Department of Genetics, Metabolism and Pediatrics, Western University, London Health Sciences Centre, London, Ontario, Canada.

    • Chitra Prasad
  52. Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.

    • Agnieszka Prytula
  53. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Patrick Rump
  54. Department of Paediatric Nephrology, Kings College London, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.

    • Manish D Sinha
  55. Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.

    • Neveen A Soliman
  56. Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.

    • Neveen A Soliman
  57. Department of Nephrology, Ibn Rochd University Hospital, Casablanca, Morocco.

    • Kenza Soulami
  58. Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, Massachusetts, USA.

    • David A Sweetser
    •  & Jessica L Waxler
  59. Division of Genetics and Metabolism, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan.

    • Wen-Hui Tsai
  60. Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.

    • Jeng-Daw Tsai
  61. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

    • Jeng-Daw Tsai
  62. Department of Pediatrics II, University Hospital Essen, Essen, Germany.

    • Udo Vester
  63. Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • David H Viskochil
  64. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

    • Nithiwat Vatanavicharn
  65. Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA.

    • Klaas J Wierenga
  66. Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Matthias T F Wolf
  67. Department of Pediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong, China.

    • Sik-Nin Wong
  68. Medical Faculty, University of Muenster, Muenster, Germany.

    • Sebastian A Leidel
  69. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Peter C Dedon
  70. Singapore–MIT Alliance for Research and Technology, Infectious Disease IRG, Singapore.

    • Peter C Dedon
  71. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Shrikant Mane
    •  & Richard P Lifton
  72. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.

    • Richard P Lifton
  73. Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Peter Kannu
    •  & David Chitayat
  74. Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.

    • Daniella Magen
  75. Department of Genetics, Necker Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France.

    • Corinne Antignac


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J.R., G. Mollet, D. Schapiro, W.T., O.G., S.A., D. Schanze, N.B., G. Martin, S.L., M.F., B.M., S.V., N.D.R., M.A., T.H., S. Shril, E.W., H.Y.G., W.-I.C., C.E.S., W.L.P., J.K.W., A.D., V.M., A.B., R.E.S., P.M.G., S.M., R.P.L., M.Z., C.A., and F.H. generated total-genome linkage data, performed exome capture with massively parallel sequencing, and performed whole-exome evaluation and mutation analysis. D.A.B. generated knockdown cell lines, performed in vitro studies (proliferation, survival, ER stress, DDR, apoptosis, and migration) in immortalized human podocytes, and performed coimmunoprecipitation experiments. D.A.B. and J.A.L. performed immunofluorescence and subcellular localization studies in tissue sections and cell lines by confocal microscopy. J.R., W.T., J.K.W., D.A.B., O.B., B. Behnam, B. Beeson, M. Bruce, G.-S.C., J.-H.C., M.T.C., P.E.G., C.K.-B., Y.-Y.K., W.-m.L., E.L., S.-P.L., R.O.L., A.M., M.M., K.N., F.O., M.P., A. Prytula, C.P., P. Rump, T.S., M.D.S., N.A.S., K. Soulami, W.-H.T., J.-D.T., D.A.S., R.T., U.V., D.H.V., N.V., J.L.W., K.J.W., M.T.F.W., S.-N.W., P.K., D.C., D.M., C.-H.C., C.-H.H., J.A.K., E.R.R., B. Callewaert, M.Z., C.A., and F.H. recruited patients and gathered detailed clinical information for the study. M.-C.D., B. Collinet, D.L., T.B., and H.v.T. performed yeast complementation experiments and 3D modeling of the KEOPS complex. I.C.G. and G. Mollet performed proteomic studies in human podocyte cell lines P. Revy performed telomere restriction-fragment assays. T.J.-S., J.M.S., C.A.H., J.F.P.U., A. Poduri, and G.T. performed zebrafish experiments and data analysis. O.S.-F. and M. Bouchard performed CRISPR–Cas9 knockout in mouse embryos and subsequent embryonic phenotyping. M.-C.D., B. Collinet, D.L., T.B., A.-C.B., S. Sanquer, and H.v.T. performed t6A analysis in Δkae1 yeast strains. P.C.D. and J.F.H. performed t6A analysis in human podocytes. K. Scharmann, S.D.K., and S.A.L. contributed to the t6A analysis. All authors critically reviewed the paper. M.Z., C.A. and F.H. conceived and directed the project and wrote the paper, with the help of D.A.B., G. Mollet, and H.v.T.

Competing interests

M.T.C., A.B., and R.E.S. are employees of GeneDx. F.H. is a cofounder of Goldfinch Biopharma, Inc. and receives royalties from Claritas Genomics. The other authors declare that they have no competing financial interests.

Corresponding authors

Correspondence to Martin Zenker or Corinne Antignac or Friedhelm Hildebrandt.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–28 and Supplementary Tables 1–3.

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Supplementary Data

    Unedited western blots.

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