Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Braun DA

PROVIDER: S-EPMC5819591 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Braun Daniela A DA Rao Jia J Mollet Geraldine G Schapiro David D Daugeron Marie-Claire MC Tan Weizhen W Gribouval Olivier O Boyer Olivia O Revy Patrick P Jobst-Schwan Tilman T Schmidt Johanna Magdalena JM Lawson Jennifer A JA Schanze Denny D Ashraf Shazia S Ullmann Jeremy F P JFP Hoogstraten Charlotte A CA Boddaert Nathalie N Collinet Bruno B Martin Gaëlle G Liger Dominique D Lovric Svjetlana S Furlano Monica M Guerrera I Chiara IC Sanchez-Ferras Oraly O Hu Jennifer F JF Boschat Anne-Claire AC Sanquer Sylvia S Menten Björn B Vergult Sarah S De Rocker Nina N Airik Merlin M Hermle Tobias T Shril Shirlee S Widmeier Eugen E Gee Heon Yung HY Choi Won-Il WI Sadowski Carolin E CE Pabst Werner L WL Warejko Jillian K JK Daga Ankana A Basta Tamara T Matejas Verena V Scharmann Karin K Kienast Sandra D SD Behnam Babak B Beeson Brendan B Begtrup Amber A Bruce Malcolm M Ch'ng Gaik-Siew GS Lin Shuan-Pei SP Chang Jui-Hsing JH Chen Chao-Huei CH Cho Megan T MT Gaffney Patrick M PM Gipson Patrick E PE Hsu Chyong-Hsin CH Kari Jameela A JA Ke Yu-Yuan YY Kiraly-Borri Cathy C Lai Wai-Ming WM Lemyre Emmanuelle E Littlejohn Rebecca Okashah RO Masri Amira A Moghtaderi Mastaneh M Nakamura Kazuyuki K Ozaltin Fatih F Praet Marleen M Prasad Chitra C Prytula Agnieszka A Roeder Elizabeth R ER Rump Patrick P Schnur Rhonda E RE Shiihara Takashi T Sinha Manish D MD Soliman Neveen A NA Soulami Kenza K Sweetser David A DA Tsai Wen-Hui WH Tsai Jeng-Daw JD Topaloglu Rezan R Vester Udo U Viskochil David H DH Vatanavicharn Nithiwat N Waxler Jessica L JL Wierenga Klaas J KJ Wolf Matthias T F MTF Wong Sik-Nin SN Leidel Sebastian A SA Truglio Gessica G Dedon Peter C PC Poduri Annapurna A Mane Shrikant S Lifton Richard P RP Bouchard Maxime M Kannu Peter P Chitayat David D Magen Daniella D Callewaert Bert B van Tilbeurgh Herman H Zenker Martin M Antignac Corinne C Hildebrandt Friedhelm F

Nature genetics 20170814 10

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 ...[more]

PMID: 28805828

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome.
| S-EPMC6159964 | biostudies-literature

Mutations in EMP2 cause childhood-onset nephrotic syndrome.
| S-EPMC4121470 | biostudies-literature

<i>MAGI2</i> Mutations Cause Congenital Nephrotic Syndrome.
| S-EPMC5407720 | biostudies-literature

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
| S-EPMC5330744 | biostudies-literature

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disoders
2022-08-11 | PXD018838 | Pride

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis.
| S-EPMC5088565 | biostudies-literature

Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.
| S-EPMC4811732 | biostudies-literature

RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.
| S-EPMC4678428 | biostudies-literature

Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome.
| S-EPMC4596915 | biostudies-literature

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
| S-EPMC3726174 | biostudies-literature