Nature genetics · 2017

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

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

Аннотация

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.

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

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