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

Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, Gribouval O, Boyer O, Revy P, Jobst-Schwan T, Schmidt JM, Lawson JA, Schanze D, Ashraf S, Ullmann JFP, Hoogstraten CA, Boddaert N, Collinet B, Martin G, Liger D, Lovric S, Furlano M, Guerrera IC, Sanchez-Ferras O, Hu JF, Boschat AC, Sanquer S, Menten B, Vergult S, De Rocker N, Airik M, Hermle T, Shril S, Widmeier E, Gee HY, Choi WI, Sadowski CE, Pabst WL, Warejko JK, Daga A, Basta T, Matejas V, Scharmann K, Kienast SD, Behnam B, Beeson B, Begtrup A, Bruce M, Ch'Ng GS, Lin SP, Chang JH, Chen CH, Cho MT, Gaffney PM, Gipson PE, Hsu CH, Kari JA, Ke YY, Kiraly-Borri C, Lai WM, Lemyre E, Littlejohn RO, Masri A, Moghtaderi M, Nakamura K, Ozaltin F, Praet M, Prasad C, Prytula A, Roeder ER, Rump P, Schnur RE, Shiihara T, Sinha MD, Soliman NA, Soulami K, Sweetser DA, Tsai WH, Tsai JD, Topaloglu R, Vester U, Viskochil DH, Vatanavicharn N, Waxler JL, Wierenga KJ, Wolf MTF, Wong SN, Leidel SA, Truglio G, Dedon PC, Poduri A, Mane S, Lifton RP, Bouchard M, Kannu P, Chitayat D, Magen D, Callewaert B, Van Tilbeurgh H, Zenker M, Antignac C, Hildebrandt F (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 49

Pages Range: 1529-1538

Journal Issue: 10

DOI: 10.1038/ng.3933

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.

Authors with CRIS profile

Involved external institutions

Tehran University of Medical Sciences (TUMS) / دانشگاه علوم پزشکی تهران Iran, Islamic Republic of (IR) University of Paris 5 - René Descartes / Université Paris V René Descartes France (FR) Boston Children's Hospital United States (USA) (US) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Hôpital Necker-Enfants malades France (FR) University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud France (FR) University Hospital Ghent Belgium (BE) Institut des maladies génétiques Imagine France (FR) McGill University Canada (CA) Mackay Hospital and Health Service (MHHS) Australia (AU) Rambam Health Care Campus Israel (IL) Max-Planck-Institut für molekulare Biomedizin / Max Planck Institute for Molecular Biomedicine Germany (DE) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Universitätsklinikum Essen Germany (DE) Oklahoma Medical Research Foundation (OMRF) United States (USA) (US) Taichung Veterans General Hospital Taiwan (TW) University of Oklahoma United States (USA) (US) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) Princess Margaret Hospital for Children Australia (AU) Iran University of Medical Sciences (IUMS) / دانشگاه علوم پزشکی ایران Iran, Islamic Republic of (IR) Evelina London Children's Hospital United Kingdom (GB) Massachusetts General Hospital United States (USA) (US) University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US) Houston Texas Medical Center United States (USA) (US) Kuala Lumpur Hospital Malaysia (MY) GeneDX United States (USA) (US) University of Michigan United States (USA) (US) University of Toronto Canada (CA) Yamagata University (YU) Japan (JP) University of Jordan Jordan (JO) Universitätsklinikum Magdeburg A.ö.R. Germany (DE) Massachusetts Institute of Technology (MIT) United States (USA) (US) Université de Montréal Canada (CA) Yale University United States (USA) (US) Chi Mei Medical Center Taiwan (TW) Mahidol University / มหาวิทยาลัยมหิดล Thailand (TH) Mackay Medical College / 馬偕醫學院 China (CN) Western University Canada (CA) University of Utah United States (USA) (US) Centre Hospitalier Universitaire Ibn Rochd / Ibn Rushd University Hospital Morocco (MA) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) Cairo University Egypt (EG) Hacettepe University Turkey (TR) Tuen Mun Hospital Hong Kong (HK)

How to cite

APA:

Braun, D.A., Rao, J., Mollet, G., Schapiro, D., Daugeron, M.-C., Tan, W.,... 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

MLA:

Braun, Daniela A., et al. "Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly." Nature Genetics 49.10 (2017): 1529-1538.

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