2. Academic Validation
  3. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

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

  • Nat Genet. 2017 Oct;49(10):1529-1538. doi: 10.1038/ng.3933.
Daniela A Braun 1,  Jia Rao 1,  Geraldine Mollet 2 3,  David Schapiro 1,  Marie-Claire Daugeron 4,  Weizhen Tan 1,  Olivier Gribouval 2 3,  Olivia Boyer 2 3 5,  Patrick Revy 3 6,  Tilman Jobst-Schwan 1,  Johanna Magdalena Schmidt 1,  Jennifer A Lawson 1,  Denny Schanze 7,  Shazia Ashraf 1,  Jeremy F P Ullmann 8 9,  Charlotte A Hoogstraten 1,  Nathalie Boddaert 3 10 11,  Bruno Collinet 4 12 13,  Gaëlle Martin 2 3,  Dominique Liger 4,  Svjetlana Lovric 1,  Monica Furlano 2 3 14,  I Chiara Guerrera 15,  Oraly Sanchez-Ferras 16,  Jennifer F Hu 17,  Anne-Claire Boschat 18,  Sylvia Sanquer 19 20,  Björn Menten 21,  Sarah Vergult 21,  Nina De Rocker 21,  Merlin Airik 1,  Tobias Hermle 1,  Shirlee Shril 1,  Eugen Widmeier 1 22,  Heon Yung Gee 1 23,  Won-Il Choi 1,  Carolin E Sadowski 1,  Werner L Pabst 1,  Jillian K Warejko 1,  Ankana Daga 1,  Tamara Basta 4,  Verena Matejas 24,  Karin Scharmann 25 26,  Sandra D Kienast 25 26,  Babak Behnam 27 28,  Brendan Beeson 29,  Amber Begtrup 30,  Malcolm Bruce 29,  Gaik-Siew Ch'ng 31,  Shuan-Pei Lin 32 33,  Jui-Hsing Chang 34,  Chao-Huei Chen 35,  Megan T Cho 30,  Patrick M Gaffney 36,  Patrick E Gipson 37,  Chyong-Hsin Hsu 34,  Jameela A Kari 38,  Yu-Yuan Ke 35,  Cathy Kiraly-Borri 39,  Wai-Ming Lai 40,  Emmanuelle Lemyre 41,  Rebecca Okashah Littlejohn 42 43,  Amira Masri 44,  Mastaneh Moghtaderi 45,  Kazuyuki Nakamura 46,  Fatih Ozaltin 47 48 49,  Marleen Praet 50,  Chitra Prasad 51,  Agnieszka Prytula 52,  Elizabeth R Roeder 42 43,  Patrick Rump 53,  Rhonda E Schnur 30,  Takashi Shiihara 46,  Manish D Sinha 54,  Neveen A Soliman 55 56,  Kenza Soulami 57,  David A Sweetser 58,  Wen-Hui Tsai 59,  Jeng-Daw Tsai 33 34 60 61,  Rezan Topaloglu 47,  Udo Vester 62,  David H Viskochil 63,  Nithiwat Vatanavicharn 64,  Jessica L Waxler 58,  Klaas J Wierenga 65,  Matthias T F Wolf 66,  Sik-Nin Wong 67,  Sebastian A Leidel 25 26 68,  Gessica Truglio 8,  Peter C Dedon 69 70,  Annapurna Poduri 8 9,  Shrikant Mane 71,  Richard P Lifton 71 72,  Maxime Bouchard 16,  Peter Kannu 73,  David Chitayat 73,  Daniella Magen 74,  Bert Callewaert 21,  Herman van Tilbeurgh 4,  Martin Zenker 7,  Corinne Antignac 2 3 75,  Friedhelm Hildebrandt 1
Affiliations

Affiliations

  • 1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Imagine Institute, Paris, France.
  • 3 Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
  • 4 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 5 Department of Pediatric Nephrology, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 6 INSERM, U1163, Imagine Institute, Laboratory of Genome Dynamics in the Immune system, Paris, France.
  • 7 Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
  • 8 Epilepsy Genetics Program and F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
  • 9 Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
  • 10 INSERM, U1163, Imagine Institute, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, and INSERM U1000, Paris, France.
  • 11 Department of Pediatric Radiology, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 12 Sorbonne Universités UPMC, UFR 927, Sciences de la Vie, Paris, France.
  • 13 Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie UMR 7590, Sorbonne Universités, UPMC, Université Paris 06, Paris, France.
  • 14 Nephrology Department, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma de Barcelona and REDINREN, Barcelona, Spain.
  • 15 Proteomics platform 3P5-Necker, Université Paris Descartes-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France.
  • 16 Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
  • 17 Departments of Chemistry and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 18 Mass Spectrometry Platform, Imagine Institute, Paris, France.
  • 19 Department of Metabolomic and Proteomic Biochemistry, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 20 INSERM UMR-S1124, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
  • 21 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • 22 Department of Medicine, Renal Division, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 23 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 24 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 25 Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
  • 26 Cells-in-Motion Cluster of Excellence, University of Muenster, Muenster, Germany.
  • 27 Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences (IUMS), Tehran, Iran.
  • 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.
  • 29 Department of Diagnostic Imaging, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia.
  • 30 GeneDx, Gaithersburg, Maryland, USA.
  • 31 Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.
  • 32 Department of Pediatric Genetics, MacKay Children's Hospital, Taipei, Taiwan.
  • 33 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
  • 34 Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.
  • 35 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.
  • 36 Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • 37 Internal Medicine and Pediatrics Divisions of Adult and Pediatric Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
  • 38 Pediatric Nephrology Center of Excellence and Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.
  • 39 Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia.
  • 40 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.
  • 41 Service de Génétique Médicale, Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
  • 42 Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas, USA.
  • 43 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 44 Department of Pediatrics, Division of Child Neurology, Faculty of Medicine, University of Jordan, Amman, Jordan.
  • 45 Chronic Kidney Disease Research Center, Tehran University of Medical Science, Tehran, Iran.
  • 46 Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
  • 47 Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Hacettepe University, Ankara, Turkey.
  • 48 Nephrogenetics Laboratory, Hacettepe University Faculty of Medicine, Hacettepe University, Ankara, Turkey.
  • 49 Hacettepe University Center for Biobanking and Genomics, Hacettepe University, Ankara, Turkey.
  • 50 Department of Pathology, Ghent University Hospital, Ghent, Belgium.
  • 51 Department of Genetics, Metabolism and Pediatrics, Western University, London Health Sciences Centre, London, Ontario, Canada.
  • 52 Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
  • 53 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 54 Department of Paediatric Nephrology, Kings College London, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • 55 Department of Pediatrics, Center of Pediatric Nephrology &Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.
  • 56 Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.
  • 57 Department of Nephrology, Ibn Rochd University Hospital, Casablanca, Morocco.
  • 58 Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, Massachusetts, USA.
  • 59 Division of Genetics and Metabolism, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan.
  • 60 Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.
  • 61 Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 62 Department of Pediatrics II, University Hospital Essen, Essen, Germany.
  • 63 Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
  • 64 Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • 65 Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA.
  • 66 Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 67 Department of Pediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong, China.
  • 68 Medical Faculty, University of Muenster, Muenster, Germany.
  • 69 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 70 Singapore-MIT Alliance for Research and Technology, Infectious Disease IRG, Singapore.
  • 71 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 72 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.
  • 73 Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 74 Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
  • 75 Department of Genetics, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
PMID: 28805828 DOI: 10.1038/ng.3933
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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