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

Nature Genetics volume 49, pages 1529–1538 (2017)Cite this article

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Abstract

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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Figure 1: Whole-exome sequencing in 32 families with GAMOS identifies recessive mutations in four genes encoding KEOPS-complex subunits (LAGE3, OSGEP, TP53RK, and TPRKB).
Figure 2: TP53RK mutations abrogate interaction with TPRKB, and GAMOS mutations do not rescue the decrease in cell proliferation rate after knockdown of OSGEP or TP53RK.
Figure 3: Knockdown of OSGEP decreases t6A levels, and knockdown of OSGEP, TP53RK, or TPRKB inhibits nascent-protein synthesis and activates the UPR.
Figure 4: Knockdown of OSGEP, TP53RK, or TPRKB in human podocytes induces DDR signaling and subsequent apoptosis.
Figure 5: OSGEP and TP53RK colocalize with the ARP2/3 complex at the lamellipodia of podocytes, and knockdown disrupts the actin cytoskeleton and impairs cell migration.

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Acknowledgements

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

  1. Daniela A Braun, Jia Rao and Geraldine Mollet: These authors contributed equally to this work.

Authors and Affiliations

  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. Department of Neurology, Epilepsy Genetics Program and F.M. Kirby Neurobiology Center, 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. Département de Pédiatrie, Service de Génétique Médicale, 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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Contributions

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.

Corresponding authors

Correspondence to Martin Zenker, Corinne Antignac or Friedhelm Hildebrandt.

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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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–28 and Supplementary Tables 1–3. (PDF 6522 kb)

Life Sciences Reporting Summary (PDF 193 kb)

Supplementary Data

Unedited western blots. (PDF 3090 kb)

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Braun, D., Rao, J., Mollet, G. et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet 49, 1529–1538 (2017). https://doi.org/10.1038/ng.3933

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