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

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

26 Sep 2023

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 dominant forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1,200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome loss-of-function variants which we propose to designate "neurodevelopmental proteasomopathies". Beside 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.

Authors

Silvestre Cuinat, Stéphane Bézieau, Wallid Deb, Sandra Mercier, Virginie Vignard, Bertrand Isidor, Sébastien Küry, Frédéric Ebstein

Bibliographic Reference
Silvestre Cuinat, Stéphane Bézieau, Wallid Deb, Sandra Mercier, Virginie Vignard, et al.. Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives. Genes & Diseases, 2023, pp.101130. ⟨10.1016/j.gendis.2023.101130⟩. ⟨hal-04264182⟩
DOI
https://doi.org/10.1016/j.gendis.2023.101130
European Project Title
UPS-NDDiag
Funding
Mutuelles AXA, I-SITE NExT
HAL Collection
['CNRS - Centre national de la recherche scientifique', 'OpenAIRE', "L'unité de recherche de l'institut du thorax (INSERM UMR1087, CNRS UMR6291)", 'ANR', 'Nantes Université', 'UFR de médecine - Nantes Université']
HAL Identifier
4264182
Institution
['Centre hospitalier universitaire de Nantes', 'Institut National de la Santé et de la Recherche Médicale', 'Nantes Université - pôle Santé']
Laboratory
['Service de Génétique Médicale [Nantes]', "ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291"]
Published in
France

Table of Contents