Molecular Pathobiology of VPS45 Bone Marrow Failure
Technical Report,01 Apr 2017,31 Mar 2019
University of Massachusetts Medical School Worcester United States
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A very severe inherited bone marrow failure BMF syndrome is caused by mutations in the endosomal-lysosomal vacuolar protein sorting regulator VPS45. Missense mutations in two highly conserved residues T224N and E238K of VPS45 were identified in several consanguineous families. All have severe congenital neutropenia SCN with neutrophil and platelet dysfunction, as well as myelofibrosis leading to multilineage BMF. We hypothesize that aberrant conformation of the mutant VPS45 protein leads to abnormal granule assembly andor transport, with consequent apoptosis and cellular dysfunction in myeloid cells and megakaryocytes. Our project uses interdisciplinary studies in cellular and mouse models to elucidate the previously unexplored molecular mechanisms for this novel form of BMF caused by VPS45 mutations, while gaining insights into other congenital BMF syndromes caused by defective vesicular transport and granules.
- Medicine and Medical Research