Molecular Pathobiology of VPS45 Bone Marrow Failure
Abstract
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 and/or 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2019
- Accession Number
- AD1094512
Entities
People
- Peter E. Newburger
Organizations
- University of Massachusetts Medical School