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

TitleMutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.
Publication TypeJournal Article
Year of Publication2017
AuthorsBraun, DA, Rao, J, Mollet, G, Schapiro, D, Daugeron, M-C, Tan, W, Gribouval, O, Boyer, O, Revy, P, Jobst-Schwan, T, Schmidt, JMagdalena, Lawson, JA, Schanze, D, Ashraf, S, Ullmann, JFP, Hoogstraten, CA, Boddaert, N, Collinet, B, Martin, G, Liger, D, Lovric, S, Furlano, M, I Guerrera, C, Sanchez-Ferras, O, Hu, JF, Boschat, A-C, Sanquer, S, Menten, B, Vergult, S, De Rocker, N, Airik, M, Hermle, T, Shril, S, Widmeier, E, Gee, HYung, Choi, W-I, Sadowski, CE, Pabst, WL, Warejko, JK, Daga, A, Basta, T, Matejas, V, Scharmann, K, Kienast, SD, Behnam, B, Beeson, B, Begtrup, A, Bruce, M, Ch'ng, G-S, Lin, S-P, Chang, J-H, Chen, C-H, Cho, MT, Gaffney, PM, Gipson, PE, Hsu, C-H, Kari, JA, Ke, Y-Y, Kiraly-Borri, C, Lai, W-M, Lemyre, E, Littlejohn, ROkashah, Masri, A, Moghtaderi, M, Nakamura, K, Ozaltin, F, Praet, M, Prasad, C, Prytula, A, Roeder, ER, Rump, P, Schnur, RE, Shiihara, T, Sinha, MD, Soliman, NA, Soulami, K, Sweetser, DA, Tsai, W-H, Tsai, J-D, Topaloglu, R, Vester, U, Viskochil, DH, Vatanavicharn, N, Waxler, JL, Wierenga, KJ, Wolf, MTF, Wong, S-N, Leidel, SA, Truglio, G, Dedon, PC, Poduri, A, Mane, S, Lifton, RP, Bouchard, M, Kannu, P, Chitayat, D, Magen, D, Callewaert, B, van Tilbeurgh, H, Zenker, M, Antignac, C, Hildebrandt, F
JournalNat Genet
Date Published2017 Oct
KeywordsAnimals, Apoptosis, Carrier Proteins, Cell Movement, CRISPR-Cas Systems, Cytoskeleton, DNA Repair, Endoplasmic Reticulum Stress, Gene Knockout Techniques, Hernia, Hiatal, Humans, Intracellular Signaling Peptides and Proteins, Metalloendopeptidases, Mice, Microcephaly, Models, Molecular, Multiprotein Complexes, Mutation, Nephrosis, Nephrotic Syndrome, Podocytes, Protein Conformation, Protein-Serine-Threonine Kinases, RNA Processing, Post-Transcriptional, RNA, Transfer, Telomere Homeostasis, Zebrafish, Zebrafish Proteins

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.

Alternate JournalNat. Genet.
PubMed ID28805828
PubMed Central IDPMC5819591
Grant ListUL1 TR001863 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
T32 ES007020 / ES / NIEHS NIH HHS / United States
P30 GM110766 / GM / NIGMS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States
K08 DK095994 / DK / NIDDK NIH HHS / United States