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

Daniela A. Braun, Jia Rao, Geraldine Mollet, David Schapiro, Marie Claire Daugeron, Weizhen Tan, Olivier Gribouval, Olivia Boyer, Patrick Revy, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Jennifer A. Lawson, Denny Schanze, Shazia Ashraf, Jeremy F.P. Ullmann, Charlotte A. Hoogstraten, Nathalie Boddaert, Bruno Collinet, Gaelle Martin, Dominique LigerSvjetlana Lovric, Monica Furlano, I. Chiara Guerrera, Oraly Sanchez-Ferras, Jennifer F. Hu, Anne Claire Boschat, Sylvia Sanquer, Björn Menten, Sarah Vergult, Nina De Rocker, 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, Tamara Basta, Verena Matejas, Karin Scharmann, Sandra D. Kienast, Babak Behnam, Brendan Beeson, Amber Begtrup, Malcolm Bruce, Gaik Siew Ch'Ng, Shuan Pei Lin, Jui Hsing Chang, Chao Huei Chen, Megan T. Cho, Patrick M. Gaffney, Patrick E. Gipson, Chyong Hsin Hsu, Jameela A. Kari, Yu Yuan Ke, Cathy Kiraly-Borri, Wai Ming Lai, Emmanuelle Lemyre, Rebecca Okashah Littlejohn, Amira Masri, Mastaneh Moghtaderi, Kazuyuki Nakamura, Fatih Ozaltin, Marleen Praet, Chitra Prasad, Agnieszka Prytula, Elizabeth R. Roeder, Patrick Rump, Rhonda E. Schnur, Takashi Shiihara, Manish D. Sinha, Neveen A. Soliman, Kenza Soulami, David A. Sweetser, Wen Hui Tsai, Jeng Daw Tsai, Rezan Topaloglu, Udo Vester, David H. Viskochil, Nithiwat Vatanavicharn, Jessica L. Waxler, Klaas J. Wierenga, Matthias T.F. Wolf, Sik Nin Wong, Sebastian A. Leidel, Gessica Truglio, Peter C. Dedon, Annapurna Poduri, Shrikant Mane, Richard P. Lifton, Maxime Bouchard, Peter Kannu, David Chitayat, Daniella Magen, Bert Callewaert, Herman Van Tilbeurgh, Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt

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131 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1529-1538
Number of pages10
JournalNature Genetics
Issue number10
Publication statusPublished - 2017 Oct 1

Bibliographical note

Funding Information:
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.

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All Science Journal Classification (ASJC) codes

  • Genetics


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