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

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; 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 Tilbeurgh; Martin Zenker; Corinne Antignac; Friedhelm Hildebrandt

doi:10.1038/ng.3933

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

Journal article

Peer reviewed

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

Geraldine Mollet, David Schapiro, Marie-Claire Daugeron, Weizhen Tan, Olivier Gribouval, Olivia Boyer, Patrick Revy, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Jennifer A. Lawson, …

Nature genetics, Vol.49(10), pp.1529-1538

01/10/2017

DOI: https://doi.org/10.1038/ng.3933

PMID: 28805828

Abstract

Life Sciences

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.

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Title: Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly
Creators - without role: Geraldine Mollet - Imagine Institute for Genetic Diseases
David Schapiro - Boston Children's Hospital
Marie-Claire Daugeron - University of Paris-Sud
Weizhen Tan - Boston Children's Hospital
Olivier Gribouval - Délégation Paris 5
Olivia Boyer - Imagine Institute for Genetic Diseases
Patrick Revy - Délégation Paris 5
Tilman Jobst-Schwan - Boston Children's Hospital
Johanna Magdalena Schmidt
Jennifer A. Lawson - Boston Children's Hospital
Denny Schanze - University Hospital Magdeburg
Shazia Ashraf - Boston Children's Hospital
Jeremy F. P. Ullmann - Boston Children's Hospital
Charlotte A. Hoogstraten - Boston Children's Hospital
Nathalie Boddaert - Délégation Paris 5
Bruno Collinet - University of Paris-Sud
Gaëlle Martin - Imagine Institute for Genetic Diseases
Dominique Liger - University of Paris-Sud
Svjetlana Lovric - Boston Children's Hospital
Monica Furlano - Imagine Institute for Genetic Diseases
I. Chiara Guerrera - Délégation Paris 5
Oraly Sanchez-Ferras - McGill University Health Centre
Jennifer F. Hu
Anne-Claire Boschat - Imagine Institute for Genetic Diseases
Sylvia Sanquer - Assistance Publique – Hôpitaux de Paris
Björn Menten - Ghent University Hospital
Sarah Vergult - Ghent University Hospital
Nina de Rocker - Ghent University Hospital
Merlin Airik - Boston Children's Hospital
Tobias Hermle - Boston Children's Hospital
Shirlee Shril - Boston Children's Hospital
Eugen Widmeier - Boston Children's Hospital
Heon Yung Gee - Boston Children's Hospital
Won-Il Choi
Carolin E. Sadowski - Boston Children's Hospital
Werner L. Pabst - Boston Children's Hospital
Jillian K. Warejko - Boston Children's Hospital
Ankana Daga - Boston Children's Hospital
Tamara Basta - University of Paris-Sud
Verena Matejas - Friedrich-Alexander-Universität Erlangen-Nürnberg
Karin Scharmann - Max Planck Institute for Molecular Biomedicine
Sandra D. Kienast - Max Planck Institute for Molecular Biomedicine
Babak Behnam - Iran University of Medical Sciences
Brendan Beeson - King Edward Memorial Hospital
Amber Begtrup - GeneDx [Gaithersburg, MD, USA]
Malcolm Bruce - King Edward Memorial Hospital
Gaik-Siew Ch'Ng - Hospital Kuala Lumpur
Shuan-Pei Lin - Mackay Memorial Hospital
Jui-Hsing Chang - Mackay Memorial Hospital
Chao-Huei Chen - Taichung Veterans General Hospital
Megan T. Cho
Patrick M. Gaffney - Oklahoma Medical Research Foundation
Patrick E. Gipson - University of Michigan–Ann Arbor
Chyong-Hsin Hsu - Mackay Memorial Hospital
Jameela A. Kari - King Abdulaziz University
Yu-Yuan Ke - Taichung Veterans General Hospital
Cathy Kiraly-Borri - Princess Margaret Hospital for Children
Wai-Ming Lai
Emmanuelle Lemyre - Centre Hospitalier Universitaire Sainte-Justine
Rebecca Okashah Littlejohn - Baylor College of Medicine
Amira Masri - University of Jordan
Mastaneh Moghtaderi - University of Tehran
Kazuyuki Nakamura - Yamagata University
Fatih Ozaltin - Hacettepe University
Marleen Praet - Ghent University Hospital
Chitra Prasad - London Health Sciences Centre
Agnieszka Prytula
Elizabeth R. Roeder - Baylor College of Medicine
Patrick Rump - University Medical Center Groningen
Rhonda E. Schnur
Takashi Shiihara - Yamagata University
Manish D. Sinha - Guy's and St Thomas' NHS Foundation Trust
Neveen A. Soliman - Cairo University
Kenza Soulami - Centre Hospitalier Universitaire Ibn Rochd
David A. Sweetser - Massachusetts General Hospital
Wen-Hui Tsai - Chi Mei Medical Center
Jeng-Daw Tsai - Mackay Medical College
Rezan Topaloglu - Hacettepe University
Udo Vester - Essen University Hospital
David H. Viskochil - University of Utah
Nithiwat Vatanavicharn - Siriraj Hospital
Jessica L. Waxler - Massachusetts General Hospital
Klaas J. Wierenga - University of Oklahoma Health Sciences Center
Matthias T. F. Wolf
Sik-Nin Wong
Sebastian A. Leidel - Max Planck Institute for Molecular Biomedicine
Gessica Truglio - Boston Children's Hospital
Peter C. Dedon - Massachusetts Institute of Technology
Annapurna Poduri - Harvard University
Shrikant Mane - Yale University
Richard P. Lifton - Yale University
Maxime Bouchard - McGill University Health Centre
Peter Kannu - University of Toronto
David Chitayat - University of Toronto
Daniella Magen - Rambam Health Care Campus
Bert Callewaert - Ghent University Hospital
Herman Tilbeurgh - Institut de Biologie Intégrative de la Cellule
Martin Zenker - University Hospital Magdeburg
Corinne Antignac - Service de Génétique Médicale [CHU Necker]
Friedhelm Hildebrandt - Howard Hughes Medical Institute
Publication Details: Nature genetics, Vol.49(10), pp.1529-1538
Publisher: Nature Publishing Group
Identifiers: 9938677608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article