Daniela A. BraunJia RaoGeraldine MolletDavid SchapiroMarie Claire DaugeronWeizhen TanOlivier GribouvalOlivia BoyerPatrick RevyTilman Jobst-SchwanJohanna Magdalena SchmidtJennifer A. LawsonDenny SchanzeShazia AshrafJeremy F.P. UllmannCharlotte A. HoogstratenNathalie BoddaertBruno CollinetGaelle MartinDominique LigerSvjetlana LovricMonica FurlanoI. Chiara GuerreraOraly Sanchez-FerrasJennifer F. HuAnne Claire BoschatSylvia SanquerBjörn MentenSarah VergultNina De RockerMerlin AirikTobias HermleShirlee ShrilEugen WidmeierHeon Yung GeeWon Il ChoiCarolin E. SadowskiWerner L. PabstJillian K. WarejkoAnkana DagaTamara BastaVerena MatejasKarin ScharmannSandra D. KienastBabak BehnamBrendan BeesonAmber BegtrupMalcolm BruceGaik Siew Ch'NgShuan Pei LinJui Hsing ChangChao Huei ChenMegan T. ChoPatrick M. GaffneyPatrick E. GipsonChyong Hsin HsuJameela A. KariYu Yuan KeCathy Kiraly-BorriWai Ming LaiEmmanuelle LemyreRebecca Okashah LittlejohnAmira MasriMastaneh MoghtaderiKazuyuki NakamuraFatih OzaltinMarleen PraetChitra PrasadAgnieszka PrytulaElizabeth R. RoederPatrick RumpRhonda E. SchnurTakashi ShiiharaManish D. SinhaNeveen A. SolimanChildren's Hospital BostonInsermUniversite Paris DescartesUniversite Paris-Sud XIHôpital Necker Enfants MaladesMedizinische Fakultät und Uniklinikum MagdeburgHarvard Medical SchoolSorbonne UniversiteUniversidad Autónoma de Barcelona, Facultad de MedicinaMcGill University, Rosalind and Morris Goodman Cancer Research CentreMassachusetts Institute of TechnologyImagine InstituteUniversity Hospital of GhentUniversität Freiburg im BreisgauYonsei University College of MedicineFriedrich-Alexander-Universität Erlangen-NürnbergMax Planck Institut für molekulare BiomedizinWestfälische Wilhelms-Universität MünsterIran University of Medical SciencesNational Human Genome Research InstituteKing Edward Memorial Hospital for WomenGeneDX, Inc.Kuala Lumpur HospitalMacKay Children's HospitalMackay Medical CollegeVeterans General Hospital-Taichung TaiwanOklahoma Medical Research FoundationUniversity of Michigan, Ann ArborKing Abdulaziz UniversityPrincess Margaret Hospital Hong KongUniversity of MontrealBaylor College of MedicineThe University of JordanTehran University of Medical SciencesYamagata University Faculty of MedicineHacettepe University, Faculty of MedicineHacettepe ÜniversitesiWestern UniversityUniversity of Groningen, University Medical Center GroningenGuy's and St Thomas' NHS Foundation TrustCairo UniversityEgyptian Group for Orphan Renal DiseasesCentre Hospitalier Universitaire Ibn-RochdMassachusetts General HospitalChi Mei Medical CenterTaipei Medical UniversityUniversitäts Klinikum Essen und Medizinische FakultätUniversity of Utah, School of MedicineMahidol UniversityUniversity of Oklahoma Health Sciences CenterUT Southwestern Medical SchoolTuen Mun HospitalSingapore-MIT AllianceYale University School of MedicineRockefeller UniversityHospital for Sick Children University of TorontoPediatric Nephrology Institute2018-12-212019-03-142018-12-212019-03-142017-10-01Nature Genetics. Vol.49, No.10 (2017), 1529-153815461718106140362-s2.0-85030166114https://repository.li.mahidol.ac.th/handle/20.500.14594/41775© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/ng.3933