title: De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.
abstract: 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.
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Küry
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Besnard
authors.affiliation: Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ebstein
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Tahir N
authors.initials: TN
authors.lastname: Khan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Computer Science, Warsaw University of Technology, Warsaw 00-661, Poland; Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica
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authors.lastname: Douglas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.affiliation: Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Xénia
authors.initials: X
authors.lastname: Latypova
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Khan
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Mathilde
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authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephanie
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authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Kimberly
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authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, 31059 Toulouse, France.
authors.forename: Eric
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authors.lastname: Bieth
authors.affiliation: Fédération de Génétique, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, 75935 Paris Cedex 19, France.
authors.forename: Laurence
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authors.affiliation: Génétique Médicale, CHU de La Réunion, 97448 Saint Pierre, La Réunion, France.
authors.forename: Marie-Line
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authors.lastname: Jacquemont
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Megan T
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authors.lastname: Cho
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
authors.forename: Elizabeth
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authors.lastname: Roeder
authors.affiliation: Département de Biochimie et Génétique, CHU d'Angers, 49933 Angers Cedex 9, France.
authors.forename: Anne-Sophie
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authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Fan
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authors.lastname: Xia
authors.affiliation: Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, Université d'Angers et Université de Nantes, 44007 Nantes, France; LabEx "Immunotherapy, Graft, Oncology," 44093 Nantes, France; Department of Dermato-cancerology, CHU de Nantes, 44093 Nantes, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Simon
authors.affiliation: Département de Biochimie et Génétique, CHU d'Angers, 49933 Angers Cedex 9, France; INSERM UMR 1083, CNRS UMR 6214, 49933 Angers Cedex 9, France.
authors.forename: Dominique
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authors.affiliation: Génétique Médicale, CHRU de Brest, 29609 Brest, France.
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authors.affiliation: Service de Génétique, CHU de Poitiers, BP 577, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86022 Poitiers Cedex, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France; CNRS UMR 6290, Université de Rennes 1, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Sylvie
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authors.lastname: Odent
authors.affiliation: Service de Génétique, CHU de Tours, 2 Boulevard Tonnellé, 37044 Tours, France; INSERM UMR U930, Faculté de Médecine, Université François Rabelais, 37044 Tours, France.
authors.forename: Annick
authors.initials: A
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authors.affiliation: Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France; CNRS UMR 6290, Université de Rennes 1, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Laurent
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authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Barbouth
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Chad A
authors.initials: CA
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Smith
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Sébastien
authors.initials: S
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authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
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authors.lastname: Deb
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
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authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
authors.forename: Sandra
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authors.lastname: Mercier
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
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authors.lastname: Vincent
authors.affiliation: Service de Génétique Médicale, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Caroline
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authors.affiliation: Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Valérie
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authors.affiliation: Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, 110231 Bogotá, Colombia.
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authors.affiliation: Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, 110231 Bogotá, Colombia.
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authors.affiliation: Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
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authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
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authors.lastname: Cogné
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
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authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
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authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
authors.forename: Evan E
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authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kyle
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: INSERM, CNRS, l'Institut du Thorax, Université de Nantes, 44007 Nantes, France; L'Institut du Thorax, CHU de Nantes, 44093 Nantes, France.
authors.forename: Richard
authors.initials: R
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Kloetzel
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France; Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, Université d'Angers et Université de Nantes, 44007 Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA; Institute of Mother and Child, Warsaw 01-211, Poland. Electronic address: pawels@bcm.edu.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France. Electronic address: bertrand.isidor@chu-nantes.fr.
authors.forename: Bertrand
authors.initials: B
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mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13
keywords: PSMD12; RPN5; intellectual disability; proteasome 26S; syndromic neurodevelopmental disorder; ubiquitin