The European Ribosomopathy Consonsortium (RiboEurope)

The ribosome is a fundamental piece of cellular machinery that is responsible for translating messages containing instructions for the synthesis of protein chains. A group of rare diseases, known as ribosomopathies, occur when inherited genetic mutations impair the synthesis and function of ribosomes. The EuroDBA consortium was created in 2012 to synergize clinical and biological researchers of the ribosomopathy Diamond-Blackfan anemia (DBA). This new phase of the consortium, titled RiboEurope, builds upon and expands our well-established transnational EuroDBA consortium and broadens the focus of the rare diseases we study to include other inherited bone marrow failures (IBMFs) linked to impaired ribosome biology. To date, we have successfully biobanked cell lines from over 100 patients that have a known ribosomopathy such as DBA or Shwachman-Diamond syndrome (SDS), as well as about 1/3 of these who remain unknown. Since the optimal management and treatment of individuals with IBMFSs depends on the right diagnosis, it is paramount that novel and rigorous diagnostic methods be established for ribosomopathies. Our goals here are to systematically solve the unsolved cases using our established pipeline and to employ systems biology approaches to map ribosomopathy gene networks. Consortium partners will continue registering and genotyping patients, generating cell lines, and expanding our established biobanks. We will subject all current patient cell lines and selected unresolved families to our well-established work pipeline which is routinely successful in identifying novel pathogenic variants underlying ribosomopathies and diseases that look like them. This work pipeline functionally characterizes cellular ribosome biology termed ribosomics and in conjunction with state-of-the-art omics techniques such as metabolomics, transcriptomics and proteomics will provide an extensive interrogation of the cellular pathways perturbed in ribosomopathy patients. We will go beyond high-throughput sequencing of individual registry patients and utilize a systems biology approach linking our sequencing observations through network biology analysis and advanced bioinformatics with the systematic integration of our comprehensive data sets obtained from our experimental work pipeline. It is known that genes underlying similar diseases tend to form connected clusters according to their participation in shared functions. Therefore, the second major goal of this consortium is to develop robust ribosomopathy disease signatures for gene variant candidate prioritization. This will permit a more targeted allocation of research efforts and to guide the development of assays at a diagnostic-grade level that are able to distinguish sub-classes of IBMFSs and diseases that clinically resemble them. Ultimately, by combining genomic and functional data in this consortium approach, a deeper understanding of the complex aetiology of ribosomopathies will be possible as well as the identification of novel genetic defects underlying ribosomopathies. This will serve clinicians to make more informed diagnoses, to predict disease severity and/or responsiveness to approved drugs and to identify novel targets for therapeutic intervention.

No additional funding sources recorded.