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

Geraldine Mollet 1, 2, 3, 4 David Schapiro Marie-Claire Daugeron 5, 6, 7, 8 Weizhen Tan Olivier Gribouval 2, 1, 3, 4 Olivia Boyer 9, 1, 3, 2, 4 Patrick Revy 2, 1, 3 Tilman Jobst-Schwan Johanna Magdalena Schmidt Jennifer A. Lawson 10 Denny Schanze 11 Shazia Ashraf Jeremy F. P. Ullmann Charlotte A. Hoogstraten Nathalie Boddaert 12, 1, 3, 13, 2 Bruno Collinet 14, 6, 15, 16 Gaëlle Martin 2, 1, 3, 4 Dominique Liger 17 Svjetlana Lovric Monica Furlano 2, 1, 3, 4 I. Chiara Guerrera 18, 1, 19 Oraly Sanchez-Ferras Jennifer F. Hu Anne-Claire Boschat 2 Sylvia Sanquer 20, 21, 22, 1, 3 Björn Menten 23 Sarah Vergult 23 Nina de Rocker Merlin Airik Tobias Hermle Shirlee Shril Eugen Widmeier Heon Yung Gee 10 Won-Il Choi Carolin E. Sadowski Werner L. Pabst Jillian K. Warejko Ankana Daga Tamara Basta 24, 6, 7, 8 Verena Matejas 25 Karin Scharmann 26 Sandra D. Kienast Babak Behnam Brendan Beeson Amber Begtrup 27 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 28, 29 Rebecca Okashah Littlejohn Amira Masri 30 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 31 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 32 Peter C. Dedon 33, 34 Annapurna Poduri Shrikant Mane 35 Richard P. Lifton 36 Maxime Bouchard Peter Kannu David Chitayat 37 Daniella Magen Bert Callewaert 38 Herman Tilbeurgh 6, 15, 16 Martin Zenker 39 Corinne Antignac 40, 4, 3, 2, 1, 13 Friedhelm Hildebrandt 41 Daniela A. Braun 10 Jia Rao
4 Laboratoire des Maladies Rénales Héréditaires
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 ARCHEE - Biologie Cellulaire des Archées
Dpt Microbio - Département Microbiologie
16 FAAM - Fonction et Architecture des Assemblages Macromoléculaires
B3S - Département Biochimie, Biophysique et Biologie Structurale
18 PPN - 3P5 - Plateforme Protéomique Necker [SFR Necker]
SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
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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Contributor : Marie-Claude Serre <>
Submitted on : Thursday, July 18, 2019 - 10:18:09 AM
Last modification on : Monday, July 20, 2020 - 12:34:52 PM

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Geraldine Mollet, David Schapiro, Marie-Claire Daugeron, Weizhen Tan, Olivier Gribouval, et al.. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nature Genetics, Nature Publishing Group, 2017, ⟨10.1038/ng.3933⟩. ⟨hal-02187752⟩



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