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

First Author  Braun DA Year  2017
Journal  Nat Genet Volume  49
Issue  10 Pages  1529-1538
PubMed ID  28805828 Mgi Jnum  J:260067
Mgi Id  MGI:6140620 Doi  10.1038/ng.3933
Citation  Braun DA, et al. (2017) Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet 49(10):1529-1538
abstractText  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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