GENETIC SCREENING TO IDENTIFY SUPPRESSORS OF DBA

Diamond-Blackfan anemia (DBA) is an extremely rare blood disease that affects children at an early age. Due to a genetic defect, patients can only produce limited amounts of their own red blood cells. Red blood cells have the essential task of supplying the body with oxygen and therefore DBA patients need to rely on regular blood transfusions every 3 weeks for survival. The only cure for DBA is the transplantation of stem cells from a healthy individual, which can be risky especially if the stem cell donation does not come from a sibling donor. DBA is caused by a mutation in a ribosomal protein gene. Ribosomal proteins build a large cellular complex called the ribosome which are the protein factories of a cell and essential for life. However, it remains to be elucidated how these mutations cause DBA exactly and why some people who carry such mutations develop the disease while others are completely healthy (silent carriers). One reason why silent carriers do not develop DBA could be that an additional mutation in another gene suppresses the red blood cell failure or a mutation in a gene that triggers it. With my fellowship project I would like to search for mutated genes that can rescue the defective generation of red blood cells in a petri dish. By using specialized stem cells and techniques, I first plan to scan the entire human genome (over 22.000 genes) to look for candidate genes that might be able to compensate for mutations that cause DBA. In a second step, I will investigate the relevance of the identified candidates for red blood cell production using reprogrammed DBA patient cells. To do this, I will grow red blood cells from the reprogrammed patient cells and assess if the identified candidate genes allow the development of healthy red blood cells. The knowledge gained from these experiments could help understand why red blood cell production fails as a result of ribosomal gene mutations in some individuals but not others. Moreover, the identification of genetic factors that restore red blood cell production could suggest novel therapeutic avenues for the treatment of DBA.

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