Neurodevelopmental disorders (NDDs) are a major public health problem, affecting more than 3% of children worldwide. Over the past few years, an increasing number of variants in genes encoding proteins of the ubiquitin-proteasome system (UPS) has been identified in patients with a NDD. The UPS is the most important intracellular non-lysosomal pathway for protein breakdown in eukaryotic cells. Although the UPS has been shown to be essential for neuronal development and function, reliable biological markers or cell/animal models that can be used for diagnostic purposes of such disorders remain to be fully determined. We have conceived the UPS-NDDiag project to address this shortcoming. Our main objective is to develop detection tools and techniques for reliable diagnosis of NDD caused by pathogenic variants of the UPS (UPS-NDDs).Thanks to an international collaborative effort, we collected and stored biological samples of 67 unrelated patients with UPS-NDD in a dedicated biobank (BioTND-UPS) and gathered clinical data including photographs that will be managed in a patient registry hosted by GestaltMatcher database. Using blood T cells, induced pluripotent stem cell (iPSC)-derived neuronal cell models and animal models, we will search for biological markers, molecular or epigenetic signatures as well as morphological and phenotypic features specific to UPS-NDDs. Based on our preliminary work, we predict the existence of overlapping pathophysiological mechanisms across genetically distinct UPS-NDDs. The medical relevance of our investigations will be steadily reinforced by the enrollment of new additional patients whose samples will be used to assess the diagnostic value of the identified biomarkers, signatures and cell features. Eventually, the phenotypic rescue assays with a few pre-selected compounds that we propose as a proof of concept should provide valuable insights for future therapeutic studies.
Neurodevelopmental disorders (NDDs) represent a heterogeneous group of conditions that persist throughout life, and affect more than 3% of individuals worldwide. NDD has a major impact on the affected individuals, families and society as a whole. Due to high-throughput sequencing, up to 50% of NDD cases are diagnosed as a monogenic cause. Our consortium specifically focuses on pathogenic variants in genes encoding components of the ubiquitin-proteasome system (UPS) associated with NDDs. The UPS ensures the selective degradation of proteins through a complex ubiquitination process involving >1,000 distinct ubiquitin ligases, which prepare these proteins for degradation by the 26S proteasome. The UPS is essential for cellular homeostasis and a vast number of genes are involved, most of them abundantly expressed in brain. It is therefore not surprising that 10-15% of NDDs have been associated with UPS dysfunction. The partners of our UPS-NDDiag consortium have identified more than 250 pathogenic or likely pathogenic variants across >30 UPS genes associated with NDD. However, the complexity of the system causes major challenges in assessing the pathogenicity of genetic variants, and good biomarkers that indicate UPS dysfunction are largely lacking, hampering diagnosis.
Our consortium is structured around six interconnected work packages. These will be addressed by six partners from five countries with complementary skills and outstanding expertise in advanced genetics, functional genomics; facial recognition for diagnosis of rare diseases; functional studies in hIPSCs, Drosophila and mice; bioinformatics; integrative analysis of multiomics, and pharmaceutical nanotechnology. In addition, 26 international collaborators join the consortium to enrich its knowledge and skills. Our main delivery is to provide reliable biomarkers and functional assays to classify UPS-related variants. Besides, UPS-NDDiag will yield therapeutic targets that may support drug development for personalized medicine and shed light on our current understanding of the overall pathogenesis of disorders related to the UPS.
