De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Sébastien Küry; Thomas Besnard; Frédéric Ebstein; Tahir N. Khan; Tomasz Gambin; Jessica Douglas; Carlos A. Bacino; Stephan J. Sanders; Andrea Lehmann; Xénia Latypova; Kamal Khan; Mathilde Pacault; Stephanie Sacharow; Kimberly Glaser; Eric Bieth; Laurence Perrin-Sabourin; Marie Line Jacquemont; Megan T. Cho; Elizabeth Roeder; Anne Sophie Denommé-Pichon; Kristin G. Monaghan; Bo Yuan; Fan Xia; Sylvain Simon; Dominique Bonneau; Philippe Parent; Brigitte Gilbert-Dussardier; Sylvie Odent; Annick Toutain; Laurent Pasquier; Deborah Barbouth; Chad A. Shaw; Ankita Patel; Janice L. Smith; Weimin Bi; Sébastien Schmitt; Wallid Deb; Mathilde Nizon; Sandra Mercier; Marie Vincent; Caroline Rooryck; Valérie Malan; Ignacio Briceño; Alberto Gómez; Kimberly M. Nugent; James B. Gibson; Benjamin Cogné; James R. Lupski; Holly A.F. Stessman; Evan E. Eichler; Kyle Retterer; Yaping Yang; Richard Redon; Nicholas Katsanis; Jill A. Rosenfeld; Peter Michael Kloetzel; Christelle Golzio; Stéphane Bézieau; Paweł Stankiewicz; Bertrand Isidor

doi:10.1016/j.ajhg.2017.01.003

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De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

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De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, Jessica Douglas, Carlos A. Bacino, Stephan J. Sanders, Andrea Lehmann, Xénia Latypova, …

American journal of human genetics, Vol.100(2), pp.352-363

100

02/02/2017

DOI: https://doi.org/10.1016/j.ajhg.2017.01.003

PMID: 28132691

Abstract

Genetics

Genetics(clinical)

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

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Title: De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder
Creators: Sébastien Küry (Author) - Centre Hospitalier Universitaire
Thomas Besnard (Author) - Centre Hospitalier Universitaire
Frédéric Ebstein (Author) - Charité – Universitätsmedizin Berlin
Tahir N. Khan (Author) - Duke University
Tomasz Gambin (Author) - Baylor College of Medicine;Warsaw University of Technology;Institute of Mother and Child
Jessica Douglas (Author) - Harvard University
Carlos A. Bacino (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Stephan J. Sanders (Author) - University of California at San Francisco
Andrea Lehmann (Author) - Charité – Universitätsmedizin Berlin
Xénia Latypova (Author) - Centre Hospitalier Universitaire
Kamal Khan (Author) - Duke University
Mathilde Pacault (Author) - Centre Hospitalier Universitaire
Stephanie Sacharow (Author) - Harvard University
Kimberly Glaser (Author) - University of Miami
Eric Bieth (Author) - Centre Hospitalier Universitaire
Laurence Perrin-Sabourin (Author) - Centre Hospitalier Universitaire
Marie Line Jacquemont (Author) - Centre Hospitalier Universitaire
Megan T. Cho (Author) - GeneDX Inc
Elizabeth Roeder (Author) - Baylor College of Medicine
Anne Sophie Denommé-Pichon (Author) - Centre Hospitalier Universitaire
Kristin G. Monaghan (Author) - GeneDX Inc
Bo Yuan (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Fan Xia (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Sylvain Simon (Author) - Centre Hospitalier Universitaire
Dominique Bonneau (Author) - Centre Hospitalier Universitaire
Philippe Parent (Author) - Centre Hospitalier Universitaire
Brigitte Gilbert-Dussardier (Author) - Centre Hospitalier Universitaire
Sylvie Odent (Author) - Centre Hospitalier Universitaire
Annick Toutain (Author) - Centre Hospitalier Universitaire
Laurent Pasquier (Author) - Centre Hospitalier Universitaire
Deborah Barbouth (Author) - University of Miami
Chad A. Shaw (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Ankita Patel (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Janice L. Smith (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Weimin Bi (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Sébastien Schmitt (Author) - Centre Hospitalier Universitaire
Wallid Deb (Author) - Centre Hospitalier Universitaire
Mathilde Nizon (Author) - Centre Hospitalier Universitaire
Sandra Mercier (Author) - Centre Hospitalier Universitaire
Marie Vincent (Author) - Centre Hospitalier Universitaire
Caroline Rooryck (Author) - Centre Hospitalier Universitaire
Valérie Malan (Author) - Centre Hospitalier Universitaire
Ignacio Briceño (Author) - Universidad Javeriana
Alberto Gómez (Author) - Universidad Javeriana
Kimberly M. Nugent (Author) - Baylor College of Medicine
James B. Gibson (Author) - Clinical and Metabolic Genetics
Benjamin Cogné (Author) - Centre Hospitalier Universitaire
James R. Lupski (Author) - Baylor College of Medicine;Texas Children's Hospital Houston
Holly A.F. Stessman (Author) - University of Washington
Evan E. Eichler (Author) - University of Washington;Howard Hughes Medical Institute
Kyle Retterer (Author) - GeneDX Inc
Yaping Yang (Author) - Baylor College of Medicine;Baylor Genetics, LLC
Richard Redon (Author) - Centre Hospitalier Universitaire
Nicholas Katsanis (Author) - Duke University
Jill A. Rosenfeld (Author) - Baylor College of Medicine
Peter Michael Kloetzel (Author) - Charité – Universitätsmedizin Berlin
Christelle Golzio (Author) - Duke University
Stéphane Bézieau (Author) - Centre Hospitalier Universitaire
Paweł Stankiewicz (Author) - Baylor College of Medicine;Baylor Genetics, LLC;Institute of Mother and Child
Bertrand Isidor (Author) - Centre Hospitalier Universitaire
Publication Details: American journal of human genetics, Vol.100(2), pp.352-363
Series: 100
Number of pages: 12
Grant note: We would like to thank all families for participating in this study. We acknowledge HUGODIMS (a Western France exome-based trio-approach project to identify genes involved in intellectual disability); funding for HUGODIMS (subject 1) is supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107). We thank Dr. Frédérique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. We thank Léa Ferrand and Emilie Le Blanc for grant and data management. We acknowledge GEM HUGO (Western France Network of Medical Genetics and Genomics). We are most grateful to the Nantes Genomics core facility (Biogenouest Genomics) for its technical support and for performing exome sequencing for subject 1 and his parents. This work was supported in part by grant U54HG006542 from the US National Human Genome Research Institute and National Heart, Lung, and Blood Institute to the Baylor Hopkins Center for Mendelian Genomics. This study made use of data generated by the DECIPHER community. A full list of centers who contributed to data generation is available at http://decipher.sanger.ac.uk and via email at decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust. M.T.C, K.G.M, and K.R. are employees of GeneDx.
Identifiers: 991005930306802656
Academic Unit: Creighton University
Language: English
Resource Type: Journal article