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Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly
Nature Genetics
  • Daniela A Braun
  • Jia Rao
  • Geraldine Mollet
  • David Schapiro
  • Marie-Claire Daugeron
  • Weizhen Tan
  • Olivier Gribouval
  • Olivia Boyer
  • Patrick Revy
  • Tilman Jobst-Schwan
  • Johanna Magdalena Schmidt
  • Jennifer A Lawson
  • Denny Schanze
  • Shazia Ashraf
  • Jeremy F P Ullmann
  • Charlotte A Hoogstraten
  • Nathalie Boddaert
  • Bruno Collinet
  • Gaëlle Martin
  • Dominique Liger
  • Svjetlana Lovric
  • Monica Furlano
  • I Chiara Guerrera
  • Oraly Sanchez-Ferras
  • Jennifer F Hu
  • Anne-Claire Boschat
  • Sylvia Sanquer
  • Björn Menten
  • Sarah Vergult
  • Nina De Rocker
  • Merlin Airik
  • Tobias Hermle
  • Shirlee Shril
  • Eugen Widmeier
  • Heon Yung Gee
  • Won-Il Choi
  • Carolin E Sadowski
  • Werner L Pabst
  • Jillian K Warejko
  • Ankana Daga
  • Tamara Basta
  • Verena Matejas
  • Karin Scharmann
  • Sandra D Kienast
  • Babak Behnam
  • Brendan Beeson
  • Amber Begtrup
  • Malcolm Bruce
  • Gaik-Siew Ch'ng
  • Shuan-Pei Lin
  • Jui-Hsing Chang
  • Chao-Huei Chen
  • Megan T Cho
  • Patrick M Gaffney
  • Patrick E Gipson
  • Chyong-Hsin Hsu
  • Jameela A Kari
  • Yu-Yuan Ke
  • Cathy Kiraly-Borri
  • Wai-Ming Lai
  • Emmanuelle Lemyre
  • Rebecca Okashah Littlejohn
  • Amira Masri
  • Mastaneh Moghtaderi
  • Kazuyuki Nakamura
  • Fatih Ozaltin
  • Marleen Praet
  • Chitra Prasad, Western University
  • Agnieszka Prytula
  • Elizabeth R Roeder
  • Patrick Rump
  • Rhonda E Schnur
  • Takashi Shiihara
  • Manish D Sinha
  • Neveen A Soliman
  • Kenza Soulami
  • David A Sweetser
  • Wen-Hui Tsai
  • Jeng-Daw Tsai
  • Rezan Topaloglu
  • Udo Vester
  • David H Viskochil
  • Nithiwat Vatanavicharn
  • Jessica L Waxler
  • Klaas J Wierenga
  • Matthias T F Wolf
  • Sik-Nin Wong
  • Sebastian A Leidel
  • Gessica Truglio
  • Peter C Dedon
  • Annapurna Poduri
  • Shrikant Mane
  • Richard P Lifton
  • Maxime Bouchard
  • Peter Kannu
  • David Chitayat
  • Daniella Magen
  • Bert Callewaert
  • Herman van Tilbeurgh
  • Martin Zenker
  • Corinne Antignac
  • Friedhelm Hildebrandt
Document Type
Article
Publication Date
10-1-2017
URL with Digital Object Identifier
https://doi.org/10.1038/ng.3933
Disciplines
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.

Citation Information
Daniela A Braun, Jia Rao, Geraldine Mollet, David Schapiro, et al.. "Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly" Nature Genetics Vol. 49 Iss. 10 (2017) p. 1529 - 1538
Available at: http://works.bepress.com/chitra-prasad/29/