Mutations in Keops-Complex Genes Cause Nephritic Syndrome With Primary Microcephaly Publisher Pubmed



Braun DA¹ ; Rao J¹ ; Mollet G^{2, 3} ; Schapiro D¹ ; Daugeron MC⁴ ; Tan W¹ ; Gribouval O^{2, 3} ; Boyer O^{2, 3, 5} ; Revy P^{3, 6} ; Jobstschwan T¹ ; Schmidt JM¹ ; Lawson JA¹ ; Schanze D⁷ ; Ashraf S¹ Show All Authors
Source: Nature Genetics Published:2017

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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.