occurs when PDGFRα monomers are activated. Role in physiology/pathology The importance of PDGFRA during development is apparent from the observation that the majority of mice lacking a functional Pdgfra gene develop a plethora of embryonic defects, some of which are lethal; the mutant mice exhibit defects in kidney glomeruli because of a lack of mesangial cells but also suffer an ill-defined blood defect characterized by thrombocytopenic, a bleeding tendency, and severe anemia which could be due to blood loss. The mice die at or shortly before birth. PDGF-A and PDGF-C seem to be the important activators of PDGFRα during development because mice lacking functional genes for both these PDGFRA activating ligands, i.e. Pdgfa/Pdgfc- double null mice show similar defects to Pdgra null mice. Mice genetically engineered to express a constitutively (i.e. continuously) activated PDGFRα mutant receptor eventually develop fibrosis in the skin and multiple internal organs. The studies suggest that PDGFRA plays fundamental roles in the development and function of mesodermal tissues, e.g., blood cells, connective tissue, and mesangial cells. Clinical significance PDGFRA mutations Myeloid and lymphoid cells Somatic mutations that cause the fusion of the PDGFRA gene with certain other genes occur in hematopoietic stem cells and cause a hematological malignancy in the clonal hypereosinophilia class of malignancies. These mutations create fused genes which encode chimeric proteins that possess continuously active PDGFRA-derived tyrosine kinase. They thereby continuously stimulate cell growth and proliferation and lead to the development of leukemias, lymphomas, and myelodysplastic syndromes that are commonly associated with hypereosinophilia and therefore regarded as a sub-type of clonal eosinophilia. In the most common of these mutations, the PDGFRA gene on human chromosome 4 at position q12 (notated as 4q12) fuses with the FIP1L1 gene also located at position 4q12. This interstitial (i.e. on the same chromosome) fusion creates a FIP1L1-PDGFRA fusion gene while usually losing intervening genetic material, typically including either the CHIC2 or LNX gene. The fused gene encodes a FIP1L1-PDGFRA protein that causes: a) chronic eosinophilia which progresses to chronic eosinophilic leukemia; b) a form of myeloproliferative neoplasm/myeloblastic leukemia associated with little or no eosinophilia; c) T-lymphoblastic leukemia/lymphoma associated with eosinophilia; d) myeloid sarcoma with eosinophilia (see FIP1L1-PDGFRA fusion genes); or e) mixtures of these presentations. Variations in the type of malignancy formed likely reflects the specific type(s) of hematopoietic stem cells that bear the mutation. The PDGFRA gene may also mutate through any one of several chromosome