Molecular Pathobiology of VPS45 Bone Marrow Failure
Abstract
Recently, a very severe, inherited bone marrow failure (BMF) syndrome was found to be caused by mutations in VPS45, a protein that regulates sorting of proteins into vacuoles and granules, which are small containers of proteins packaged within membranes inside cells. The children suffer from recurrent, life-threatening infections and die at age 3 months to 3 years if not treated by bone marrow transplantation. All have severely low numbers of neutrophils (white blood cells that provide defense against bacterial and fungal infection), abnormal function of neutrophil and platelet dysfunction, and myelofibrosis (scarring of the bone marrow), leading to further BMF involving multiple types of blood cells. VPS45 regulates the transport and assembly of protein complexes, termed SNAREs. Normal function of both neutrophils and platelets requires formation, mobilization, and fusion of granules; when dysregulated, these defects lead to an "intracellular traffic jam." Hypothesis: Aberrant conformation of mutant VPS45 protein pathologically stabilizes SNARE complexes in bone marrow cells, leading to abnormal granule assembly and/or transport, with consequent cell death leading to BMF. Specific Aims: (1) Determine the molecular consequences of VPS45 dysfunction in neutrophils derived from mouse embryonic stem cells. (2) Determine the functional consequences of VPS45 dysfunction in neutrophils derived from mouse embryonic stem cells. (3) Test the functional and physiological consequences of VPS45 dysfunction in mouse models of VPS45-related BMF. In the short term, the proposed studies will elucidate the previously unexplored molecular mechanisms for the novel form of BMF caused by VPS45 mutations, with potential application to other congenital BMF syndromes due to defective formation and transport of granules. The focus will be on understanding the molecular basis of BMF in this disease; also, in the long term, identification of relevant pathways should provide targets for future translational research on potential therapies. Distinguishing between the molecular effects of the specific mutations versus diminished protein content will inform future gene therapy approaches of gene editing versus replacement.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710110
Entities
People
- Peter Newburger
Organizations
- United States Army
- University of Massachusetts Medical School