Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in Correspondence should be addressed to: Martin Zenker, M.D., Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany, Phone: +49 391 67 15064, martin.zenker@med.ovgu.de or Corinne Antignac, M.D., Ph.D., INSERM U1163, Institut Imagine, 24, bd du Montparnasse, 75015 Paris, France, Phone: +33 1 42 75 43 45, corinne.antignac@inserm.fr or Friedhelm Hildebrandt, M.D., Boston Children’s Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA, Phone: +1 617-355 6129, Fax: +1 617-730 0569, friedhelm.hildebrandt@childrens.harvard.edu. *These authors contributed equally to this work. ACCESSION NUMBERS LAGE3 (NM_006014.4), OSGEP (NM_017807.3), TP53RK (NM_033550.3), TPRKB (NM_016058.2). Competing interests statement M.T.C., A.B., and R.E.S. are employees of GeneDx, Gaithersburg, MD, USA. The other authors declare that they have no competing financial interests. AUTHOR CONTRIBUTIONS 1. J.R., G.M., D.S., W.T., O.G., S.A., De.S., N.B., Ga.M., S.L., M.F., B.M., S.V., N.dR., M.A., T.H., S.S., E.W., H.Y.G., W.I.C., C.E.S., W.L.P., J.W., A.D., W.M., A.B., R.E.S., S.M., R.P.L., M.Z., C.A. and F.H. generated total genome linkage data, performed exome capture with massively parallel sequencing, and performed whole exome evaluation and mutation analysis. 2. D.A.B. generated knockdown cell lines, performed in-vitro studies (proliferation, survival, apoptosis, and migration) in immortalized human podocytes, and performed co-immunoprecipitation experiments. 3. D.A.B. and J.A.L. performed immunofluorescence and subcellular localization studies in tissue sections and cell lines by confocal microscopy. 4. J.R., W.T., J.W., D.A.B., O.B., Ba.B., Br.B., Ma.B., G.S.C.,J.H.C., M.T.C., P.G., C.K.B., Y.Y.K., W.M.L., E.L., S.P.L., R.O.L., A.M., M.M., K.N., M.P., A.P., C.P., P.R., T.S., M.S., N.A.S., K.S., W.H.T., J.D.T., Da.S., M.H.T., U.V., D.H.V., N.V., J.L.W., M.T.F.W., S.N.W., P.K., D.C., D.M., B.C., M.Z., C.A., and F.H. recruited patients and gathered detailed clinical information for the study. 5. M.C.D., Br.C., D.L., T.B.L., and H.V.T. performed yeast complementation experiments, and 3D modeling of the KEOPS complex. 6. I.C.G. and G.M. performed proteomic studies in human podocyte cell lines 7. P.R. performed telomere restriction fragment assay 8. T.J.S., J.M.S., A.P., and G.T. performed zebrafish experiments and data analysis. 9. O.S.F. and M.B. performed CRISPR/Cas9 knockout in mouse embryos and subsequent embryonic phenotyping. 10. All authors critically reviewed the paper. 11. M.Z., C.A. and F.H. conceived of and directed the project and wrote the paper, with the help of D.A.B., G.M. and H.V.T. HHS Public Access Author manuscript Nat Genet. Author manuscript; available in PMC 2018 April 01. Published in final edited form as: Nat Genet. 2017 October ; 49(10): 1529–1538. doi:10.1038/ng.3933. A uhor M anscript