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Am J Hum Genet. 2017 Feb 2;100(2):352-363. doi: 10.1016/j.ajhg.2017.01.003. Epub 2017 Jan 26.

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

Author information

1
Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
2
Institute of Biochemistry, Charité Universitätsmedizin Berlin, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
3
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
4
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.
5
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston TX, 77030, USA.
7
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
9
Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, 31059 Toulouse, France.
10
Fédération de Génétique, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, 75935 Paris Cedex 19, France.
11
Génétique Médicale, CHU de La Réunion, 97448 Saint Pierre, La Réunion, France.
12
GeneDx, Gaithersburg, MD 20877, USA.
13
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.
14
Département de Biochimie et Génétique, CHU d'Angers, 49933 Angers Cedex 9, France.
15
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.
16
Département de Biochimie et Génétique, CHU d'Angers, 49933 Angers Cedex 9, France; INSERM UMR 1083, CNRS UMR 6214, 49933 Angers Cedex 9, France.
17
Génétique Médicale, CHRU de Brest, 29609 Brest, France.
18
Service de Génétique, CHU de Poitiers, BP 577, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86022 Poitiers Cedex, France.
19
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.
20
Service de Génétique, CHU de Tours, 2 Boulevard Tonnellé, 37044 Tours, France; INSERM UMR U930, Faculté de Médecine, Université François Rabelais, 37044 Tours, France.
21
Service de Génétique Médicale, CHU de Bordeaux, 33076 Bordeaux, France.
22
Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
23
Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, 110231 Bogotá, Colombia.
24
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
25
Clinical and Metabolic Genetics, 'Specially for Children, Austin, TX 78723, USA.
26
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.
27
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
28
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
29
INSERM, CNRS, l'Institut du Thorax, Université de Nantes, 44007 Nantes, France; L'Institut du Thorax, CHU de Nantes, 44093 Nantes, France.
30
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
31
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
32
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.
33
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.
34
Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France. Electronic address: bertrand.isidor@chu-nantes.fr.

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.

KEYWORDS:

PSMD12; RPN5; intellectual disability; proteasome 26S; syndromic neurodevelopmental disorder; ubiquitin

PMID:
28132691
PMCID:
PMC5294671
DOI:
10.1016/j.ajhg.2017.01.003
[Indexed for MEDLINE]
Free PMC Article

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