Disease:


  • OMIM ID: 607686 . 607686
  • OMIM diseaseName:
  • OMIM diseaseClinical_Synopsis:
  • OMIM diseaseText: CLONING In an analysis of DNA from a patient with idiopathic hypereosinophilic syndrome (HES; 607685) in whom a complex chromosomal rearrangement had been identified, Cools et al. (2003) identified an interstitial deletion on chromosome 4q12 that resulted in fusion of the platelet-derived growth factor receptor-alpha gene (PDGFRA; 173490) to a gene encoding a putative 520-amino acid protein that most closely resembled Fip1, an essential component of the polyadenylation machinery of S. cerevisiae (Preker et al., 1995). Cools et al. (2003) therefore designated the gene Fip1-like-1 (FIP1L1). Data derived from EST database searches indicated that FIP1L1 is widely expressed and undergoes alternative splicing. Griffin et al. (2003) also found the 4q12 deletion in patients with HES, resulting in the same fusion gene involving PDGFRA and FIP1L1. They suggested that FIP1L1 be referred to as RAG (rearranged in hypereosinophilia). GENE FUNCTION - FIP1L1-PDGFRA Fusion Protein Cools et al. (2003) determined that the FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib. The FIP1L1-PDGFRA fusion gene is in-frame and fuses the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA. Griffin et al. (2003) demonstrated that the FIP1L1-PDGFRA fusion kinase is constitutively phosphorylated and supports IL3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing the fusion protein were ablated by imatinib and 2 other inhibitors of PDGFRA. Stover et al. (2006) stated that several variations of the FIP1L1/PDGFRA fusion protein have been identified in clinical studies of HES and systemic mast cell disease, but in all disease-associated cases, the autoinhibitory juxtamembrane (JM) domain of PDGFRA has been disrupted. By examining the kinase activity of several FIP1L1/PDGFRA fusion proteins, they determined that the FIP1L1 sequence was completely dispensable for PDGFRA activation in vitro and in vivo. On the other hand, N-terminal truncation of PDGFRA between 2 conserved tryptophan residues in the JM region was required for kinase activation and transforming potential of FIP1L1/PDGFRA. The presence of a complete JM domain in the FIP1L1/PDGFRA fusion protein inhibited activation of PDGFRA kinase activity. MAPPING The FIP1L1 gene maps to chromosome 4q12 (Cools et al., 2003; Griffin et al., 2003). MOLECULAR GENETICS Cools et al. (2003) and Griffin et al. (2003) identified an interstitial deletion on chromosome 4q12 in patients with HES that resulted in fusion of the FIP1L1 gene with exon 12 of the PDGFRA gene.
  • OMIM diseaseSee_Also:
  • OMIM diseaseAllelic_Variants:
  • OMIM diseaseCreation_Date: Victor A. McKusick: 4/10/2003
  • OMIM diseaseEdit_History_Data: mgross: 07/07/2006 mgross: 7/7/2006 terry: 7/6/2006 cwells: 7/23/2003 carol: 4/11/2003 tkritzer: 4/11/2003
  • OMIM diseaseContributors: Patricia A. Hartz - updated: 7/6/2006 Victor A. McKusick - updated: 7/23/2003
  • OMIM diseaseReference: 1. Cools, J.; DeAngelo, D. J.; Gotlib, J.; Stover, E. H.; Legare, R. D.; Cortes, J.; Kutok, J.; Clark, J.; Galinsky, I.; Griffin, J. D.; Cross, N. C. P.; Tefferi, A.; and 14 others: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. New Eng. J. Med. 348: 1201-1214, 2003. 2. Griffin, J. H.; Leung, J.; Bruner, R. J.; Caligiuri, M. A.; Briesewitz, R.: Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc. Nat. Acad. Sci. 100: 7830-7835, 2003. 3. Preker, P. J.; Lingner, J.; Minvielle-Sebastia, L.; Keller, W. : The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase. Cell 81: 379-389, 1995. 4. Stover, E. H.; Chen, J.; Folens, C.; Lee, B. H.; Mentens, N.; Marynen, P.; Williams, I. R.; Gilliland, D. G.; Cools, J.: Activation of FIP1L1-PDGFR-alpha requires disruption of the juxtamembrane protein of PDGFR-alpha and is FIP1L1-independent. Proc. Nat. Acad. Sci. 103: 8078-8083, 2006.