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Review Article | Open Access

Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives

Silvestre Cuinata,bStéphane Bézieaua,bWallid Deba,bSandra Merciera,bVirginie Vignarda,bBertrand Isidora,bSébastien Kürya,bFrédéric Ebsteinb( )
Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes F-44000, France
Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France

Peer review under responsibility of Chongqing Medical University.

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Abstract

The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the mendelian forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate “neurodevelopmental proteasomopathies”. Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.

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Genes & Diseases
Article number: 101130
Cite this article:
Cuinat S, Bézieau S, Deb W, et al. Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives. Genes & Diseases, 2024, 11(6): 101130. https://doi.org/10.1016/j.gendis.2023.101130

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Received: 15 May 2023
Revised: 30 July 2023
Accepted: 19 August 2023
Published: 26 September 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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