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Article Dans Une Revue American Journal of Human Genetics Année : 2017

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

1 Service de génétique médicale - Unité de génétique clinique [Nantes]
2 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
3 Duke University Medical Center
4 Warsaw University of Technology [Warsaw]
5 Boston Children's Hospital
6 BCM - Baylor College of Medicine
7 UC San Francisco - University of California [San Francisco]
8 University of Miami
9 Service Génétique Médicale [CHU Toulouse]
10 Hôpital Robert Debré
11 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
12 GeneDx [Gaithersburg, MD, USA]
13 CHU Angers - Centre Hospitalier Universitaire d'Angers
14 LabEX IGO Immunothérapie Grand Ouest
15 CRCINA-ÉQUIPE 3 - Anti-Tumor Immunosurveillance and Immunotherapy
16 CHU Nantes - Centre Hospitalier Universitaire de Nantes
17 Service de génétique [Angers]
18 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
19 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
20 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
21 IGDR - Institut de Génétique et Développement de Rennes
22 Service de génétique clinique [Rennes]
23 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
24 Service de génétique [Tours]
25 iBraiN - Imaging, Brain & Neuropsychiatry
26 CHU Bordeaux
27 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
28 PUJ - Pontificia Universidad Javeriana
29 University of Washington [Seattle]
30 Howard Hughes Medical Institute [Seattle]
31 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
Caroline Rooryck
  • Fonction : Auteur
James B. Gibson
  • Fonction : Auteur
Paweł Stankiewicz
  • Fonction : Auteur correspondant

Résumé

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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Dates et versions

hal-01478814 , version 1 (13-07-2018)

Identifiants

Citer

Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, et al.. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder. American Journal of Human Genetics, 2017, 100 (2), pp.352-363. ⟨10.1016/j.ajhg.2017.01.003⟩. ⟨hal-01478814⟩
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