Journal
NATURE GENETICS
Volume 49, Issue 10, Pages 1529-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3933
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Categories
Funding
- National Institutes of Health [DK076683]
- Howard Hughes Medical Institute
- ASN Foundation for Kidney Research
- National Human Genome Research Institute, National Institutes of Health
- German National Academy of Sciences Leopoldina [LPDS-2015-07]
- National Research Foundation of Korea, Ministry of Science, ICT and Future planning [2015R1D1A1A01056685]
- Yonsei University College of Medicine [2015-32-0047]
- NIH [K08-DK095994-05]
- Children's Clinical Research Advisory Committee (CCRAC)
- Children's Medical Center, Dallas
- Fonds de la Recherche du Quebec-Sante (FRQS)
- Canadian Institutes for Health Research [MOP-84470]
- KRESCENT
- McGill Integrated Cancer Research Training (MICRTP)
- Deutsche Forschungsgemeinschaft (DFG) [Jo 1324/1-1]
- German Research Foundation, DFG [HE 7456/1-1]
- Agence Nationale de la Recherche [ANR-12-BSV1-0033.01]
- European Union's Seventh Framework Programme [305608-EURenOmics]
- Fondation Recherche Medicale [DEQ20150331682]
- 'Investissements d'avenir' program [ANR-10-IAHU-01]
- Spanish Society of Nephrology
- Catalan Society of Nephrology
- Department of Health by National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- Deutsche Forschungsgemeinschaft [SFB423]
- Singapore National Research Foundation under the Singapore-MIT Alliance for Research and Technology
- National Institute of Environmental Health Science [ES017010, ES022858, ES002109]
- National Science Foundation [MCB-1412379]
- European Community's Seventh Framework Programme [2012305608]
- Hacettepe University [06A101008]
- COBRE [P30 GM110766]
- Dutch Kidney Foundation
- Max Planck Society
- European Research Council [ERC-2012-StG310489-tRNAmodi]
- Boston Children's Hospital
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0033] Funding Source: Agence Nationale de la Recherche (ANR)
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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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