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

作　　者：Silvestre Cuinat Stephane Bezieau Wallid Deb Sandra Mercier Virginie Vignard Bertrand Isidor Sebastien Kury Frederic Ebstein 

机构地区：[1]Nantes Universite,CHU Nantes,Service de Genetique Medicale,Nantes F-44000,France [2]Nantes Universite,CHU Nantes,CNRS,INSERM,l'institut du thorax,Nantes F-44000,France

出　　处：《Genes & Diseases》2024年第6期168-191,共24页基因与疾病（英文）

基　　金：supported by the European Joint Programme on Rare Diseases (EJP RD)for the project"UPS-NDDiag"and the Agence Nationale de la Recherche (ANR)for the project ANR-21-CE17-0005.

摘　　要：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 dis-eases.Strikingly,a substantial fraction of the mendelian forms of intellectual disability is asso-ciated 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"neurodevelopmen-tal 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 mo-lecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined.In this re-view,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.

关 键 词：Biomarkers Loss-of-function variants Neurodevelopmental disorders PROTEASOME Rare diseases Therapeutic targets 

分 类 号：R74[医药卫生—神经病学与精神病学]