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 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France
  • 4 Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France
  • 5 Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany
  • 6 Epilepsy Genetics Program and F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA
  • 7 Proteomics platform 3P5-Necker, Université Paris Descartes-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France
  • 8 Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada
  • 9 Departments of Chemistry and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  • 10 Mass Spectrometry Platform, Imagine Institute, Paris, France
  • 11 Department of Metabolomic and Proteomic Biochemistry, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  • 12 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  • 13 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • 14 Max Planck Institute for Molecular Biomedicine, Muenster, Germany
  • 15 Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences (IUMS), Tehran, Iran
  • 16 Department of Diagnostic Imaging, Princess Margaret and King Edward Memorial Hospitals, Perth, Western Australia, Australia
  • 17 GeneDx, Gaithersburg, Maryland, USA
  • 18 Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
  • 19 Department of Pediatric Genetics, MacKay Children's Hospital, Taipei, Taiwan
  • 20 Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan
  • 21 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
  • 22 Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  • 23 Internal Medicine and Pediatrics Divisions of Adult and Pediatric Nephrology, University of Michigan, Ann Arbor, Michigan, USA
  • 24 Pediatric Nephrology Center of Excellence and Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia
  • 25 Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia
  • 26 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
  • 27 Service de Génétique Médicale, Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada
  • 28 Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas, USA
  • 29 Department of Pediatrics, Division of Child Neurology, Faculty of Medicine, University of Jordan, Amman, Jordan
  • 30 Chronic Kidney Disease Research Center, Tehran University of Medical Science, Tehran, Iran
  • 31 Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
  • 32 Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Hacettepe University, Ankara, Turkey
  • 33 Department of Pathology, Ghent University Hospital, Ghent, Belgium
  • 34 Department of Genetics, Metabolism and Pediatrics, Western University, London Health Sciences Centre, London, Ontario, Canada
  • 35 Department of Pediatrics, Ghent University Hospital, Ghent, Belgium
  • 36 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 37 Department of Paediatric Nephrology, Kings College London, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
  • 38 Department of Pediatrics, Center of Pediatric Nephrology &Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
  • 39 Department of Nephrology, Ibn Rochd University Hospital, Casablanca, Morocco
  • 40 Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, Massachusetts, USA
  • 41 Division of Genetics and Metabolism, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan
  • 42 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
  • 43 Department of Pediatrics II, University Hospital Essen, Essen, Germany
  • 44 Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA
  • 45 Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • 46 Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
  • 47 Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  • 48 Department of Pediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong, China
  • 49 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  • 50 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
  • 51 Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  • 52 Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel
Nat. Genet., 2017 Oct;49(10):1529-1538.
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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.