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.

Ribosomes are very small structures found in cells with the crucial role of making proteins. Ribosomes have two main components called the large subunit and the small subunit that come together when the ribosome is ready to make a new protein. Both the large and the small subunits are themselves also composed by defined proteins called ribosomal proteins (RP) and molecules of RNA called ribosomal RNA (rRNA). Ribosomes need to synthesize hundreds of different proteins and they do so by a process called translation where the genetic information in the form of messenger RNA (mRNA) is turning into a sequence of amino-acids that constitute the protein. In humans, defects in ribosome production or function resulting in a deficit of protein translation lead to a heterogeneous group of human disorders called ribosomopathies, which have significant morbidity associated. Ribosomopathies are usually characterized by anaemia (a decrease in the number of red blood cells) together with growth retardation and developmental abnormalities, and although ribosomes are present and function in all cell types, the predominant manifestation of ribosomopathy is a defect during erythropoiesis, the production of red blood cells. The most studied ribosomopathy is the Diamond-Blackfan Anaemia (DBA), a rare disease that is present from birth. DBA is characterized by the presence of anaemia and increased susceptibility to cancer in the patients. Approximately 70% of DBA patients are found to harbour mutations in genes that encode ribosomal proteins. However, recent studies have uncovered a group of non-ribosomal proteins that can potentially cause DBA when dysregulated. The group of Kaan Boztug at the St. Anna Children's Cancer Research Institute (CCRI) identified novel mutations in a gene encoding for a non-ribosomal protein as the cause of DBA in a patient. The Boztug lab has since then investigated the precise role of the non-ribosomal protein in ribosome formation and function. Through large-scale quantification of numerous biomolecules and the use of e.g. cellular models, this study aimed to comprehensively dissect the function of the non-ribosomal protein on ribosomal biology, and secondly to investigate its contribution and impact on the DBA disease when dysregulated. Studies like this are crucial not only to understand the role of non-ribosomal proteins in ribosome biology, but also to uncover their complex interplay with ribosomes under both normal and pathological conditions. Furthermore, these studies can provide new strategies for the diagnosis, prevention, and treatment of human ribosomopathies.