PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.


Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
06 Jun 2024
Historique:
received: 01 11 2023
revised: 15 05 2024
accepted: 16 05 2024
medline: 13 6 2024
pubmed: 13 6 2024
entrez: 12 6 2024
Statut: aheadofprint

Résumé

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6, which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health.

Identifiants

pubmed: 38866022
pii: S0002-9297(24)00179-4
doi: 10.1016/j.ajhg.2024.05.016
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests A.C. and K.M. are employees of GeneDx, LLC. J.R.L. has stock in 23andMe and is a paid consultant for Genome International.

Auteurs

Wallid Deb (W)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Cory Rosenfelt (C)

Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada.

Virginie Vignard (V)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Jonas Johannes Papendorf (JJ)

Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany.

Sophie Möller (S)

Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany.

Martin Wendlandt (M)

Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany.

Maja Studencka-Turski (M)

Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany.

Benjamin Cogné (B)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Thomas Besnard (T)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Léa Ruffier (L)

Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Bérénice Toutain (B)

Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Léa Poirier (L)

Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Silvestre Cuinat (S)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Amy Kritzer (A)

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA, USA.

Amy Crunk (A)

GeneDx, Gaithersburg, MD 20877, USA.

Janette diMonda (J)

Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.

Jaime Vengoechea (J)

Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.

Sandra Mercier (S)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Lotte Kleinendorst (L)

Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Mieke M van Haelst (MM)

Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Human Genetics, Amsterdam UMC, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands.

Linda Zuurbier (L)

Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Human Genetics, Amsterdam UMC, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands.

Telma Sulem (T)

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Hildigunnur Katrínardóttir (H)

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Rún Friðriksdóttir (R)

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Patrick Sulem (P)

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Kari Stefansson (K)

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Berglind Jonsdottir (B)

Childrens Hospital Hringurinn, National University Hospital of Iceland, Reykjavik, Iceland.

Shimriet Zeidler (S)

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.

Margje Sinnema (M)

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

Alexander P A Stegmann (APA)

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

Natali Naveh (N)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Cara M Skraban (CM)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Departments of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Christopher Gray (C)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Jill R Murrell (JR)

Department of Pathology and Laboratory Medicine, Children's Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Sedat Isikay (S)

Division of Pediatric Neurology, Department of Pediatrics, Gaziantep Islam, Science and Technology University Faculty of Medicine, Gaziantep, Türkiye.

Davut Pehlivan (D)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX 77030, USA.

Daniel G Calame (DG)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX 77030, USA.

Jennifer E Posey (JE)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Mathilde Nizon (M)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Kirsty McWalter (K)

GeneDx, Gaithersburg, MD 20877, USA.

James R Lupski (JR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Bertrand Isidor (B)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

François V Bolduc (FV)

Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada.

Stéphane Bézieau (S)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Elke Krüger (E)

Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany. Electronic address: elke.krueger@uni-greifswald.de.

Sébastien Küry (S)

Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.

Frédéric Ebstein (F)

Nantes Université, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France; Institut für Medizinische Biochemie und Molekularbiologie (IMBM), Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany. Electronic address: frederic.ebstein@univ-nantes.fr.

Classifications MeSH