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

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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
Volume49
Issue number10
DOIs
Publication statusPublished - 2017 Oct 1

All Science Journal Classification (ASJC) codes

  • Genetics

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    Braun, D. A., Rao, J., Mollet, G., Schapiro, D., Daugeron, M. C., Tan, W., Gribouval, O., Boyer, O., Revy, P., Jobst-Schwan, T., Schmidt, J. M., Lawson, J. A., Schanze, D., Ashraf, S., Ullmann, J. F. P., Hoogstraten, C. A., Boddaert, N., Collinet, B., Martin, G., ... Hildebrandt, F. (2017). Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly. Nature Genetics, 49(10), 1529-1538. https://doi.org/10.1038/ng.3933