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; William J Craigen; 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

Journal article

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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, William J Craigen, Stephan J Sanders, Andrea Lehmann, …

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

2017-02-02

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

PMCID: PMC5294671

PMID: 28132691

Abstract

PSMD12

RPN5

proteasome 26S

intellectual disability

ubiquitin

syndromic neurodevelopmental disorder

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.782 Proteasome
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder
Creators: Sébastien Küry - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Thomas Besnard - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Frédéric Ebstein - Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany
Tahir N Khan - Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA
Tomasz Gambin - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Jessica Douglas - Division of Genetics and Genomics, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Carlos A Bacino - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
William J Craigen - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Stephan J Sanders - Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Andrea Lehmann - Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany
Xénia Latypova - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Kamal Khan - Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA
Mathilde Pacault - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Stephanie Sacharow - Division of Genetics and Genomics, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Kimberly Glaser - Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Eric Bieth - Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, 31059 Toulouse, France
Laurence Perrin-Sabourin - Fédération de Génétique, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris, 75935 Paris Cedex 19, France
Marie-Line Jacquemont - Génétique Médicale, CHU de La Réunion, 97448 Saint Pierre, La Réunion, France
Megan T Cho - GeneDx, Gaithersburg, MD 20877, USA
Elizabeth Roeder - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Anne-Sophie Denommé-Pichon - Département de Biochimie et Génétique, CHU d’Angers, 49933 Angers Cedex 9, France
Kristin G Monaghan - GeneDx, Gaithersburg, MD 20877, USA
Bo Yuan - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Fan Xia - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Sylvain Simon - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, Université d’Angers et Université de Nantes, 44007 Nantes, France
Dominique Bonneau - Département de Biochimie et Génétique, CHU d’Angers, 49933 Angers Cedex 9, France
Philippe Parent - Génétique Médicale, CHRU de Brest, 29609 Brest, France
Brigitte Gilbert-Dussardier - Service de Génétique, CHU de Poitiers, BP 577, 86021 Poitiers, France
Sylvie Odent - Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France
Annick Toutain - Service de Génétique, CHU de Tours, 2 Boulevard Tonnellé, 37044 Tours, France
Laurent Pasquier - Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France
Deborah Barbouth - Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Chad A Shaw - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Ankita Patel - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Janice L Smith - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Weimin Bi - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Sébastien Schmitt - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Wallid Deb - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Mathilde Nizon - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Sandra Mercier - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Marie Vincent - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Caroline Rooryck - Service de Génétique Médicale, CHU de Bordeaux, 33076 Bordeaux, France
Valérie Malan - Service d’Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, 75015 Paris, France
Ignacio Briceño - Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, 110231 Bogotá, Colombia
Alberto Gómez - Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, 110231 Bogotá, Colombia
Kimberly M Nugent - Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA
James B Gibson - Clinical and Metabolic Genetics, ‘Specially for Children, Austin, TX 78723, USA
Benjamin Cogné - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
James R Lupski - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Holly A.F Stessman - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Evan E Eichler - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Kyle Retterer - GeneDx, Gaithersburg, MD 20877, USA
Yaping Yang - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Richard Redon - INSERM, CNRS, l’Institut du Thorax, Université de Nantes, 44007 Nantes, France
Nicholas Katsanis - Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA
Jill A Rosenfeld - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Peter-Michael Kloetzel - Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany
Christelle Golzio - Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA
Stéphane Bézieau - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Paweł Stankiewicz - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Bertrand Isidor - Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France
Publication Details: American journal of human genetics, Vol.100(2), pp.352-363
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 28132691
PMCID: PMC5294671
Record Identifier: 991031577638702976