The so-called KEOPS protein complex has been implicated in a range of functions. Among others, it regulates a chemical modification of tRNA which ensures accurate translation, and it also acts in the control of genome maintenance and DNA damage-response processes. Variants in OSGEP, TP53RK, TPRKB and LAGE3, the genes encoding the four subunits of the KEOPS complex, have now been identified to be associated with the human disorder of Galloway-Mowat syndrome (GOWAS). This is a very rare, autosomal-recessively inherited disease characterized by a combination of early-onset nephrotic syndrome, primary microcephaly, developmental delay and structural brain anomalies.

As a large international research group including the team of Martin Zenker, director of the Institute of Human Genetics at the University of Magdeburg, now reports in Nature Genetics, they studied 91 patients with GOWAS and discovered recessive mutations in the KEOPS genes in 37 individuals from 32 families. In their functional analyses using, for example, CRISPR-Cas9 knockout in zebrafish and mice, they then investigated the effects of the loss of protein function resulting from the identified mutations. They found that inactivation of the genes recapitulated the human phenotype in the animal models and caused disturbed translation, endosplasmic reticulum stress, activated DNA-damage-response signaling and ultimately apoptosis. Knockdown of OSGEP and TP53RK resulted in defects in the actin cytoskeleton and a decrease of human podocyte migration rate, which is also a manifestation in the development of nephrotic syndrome. With they work, the researchers thus established a link between KEOPS complex function and human disease and they identified four novel genes associated with Galloway-Mowat syndrome.