Two independent studies have identified recessive mutations in the endosomal trafficking gene VPS45 as the cause of a rare congenital syndrome characterized by severe neutropenia, bone marrow fibrosis, nephromegaly and susceptibility to life-threatening bacterial infections. Dror Mevorach and colleagues (Blood doi:10.1182/blood-2012-12-475566, 22 April 2013) performed homozygosity mapping and exome sequencing on two Palestinian families with this syndrome and identified a homozygous missense mutation in VPS45 present in both families. Raz Somech and colleagues (N. Engl. J. Med. doi:10.1056/NEJMoa1301296, 5 June 2013) performed similar analyses on four Palestinian families and identified the same homozygous missense mutation in VPS45 in all four families. They also analyzed a fifth affected family from Morocco and identified a different homozygous missense mutation in VPS45. Both groups also analyzed cells from affected individuals and observed defects in intracellular trafficking and increased rates of apoptosis. VPS45 encodes a protein that interacts with multiple components of the endocytic and secretory pathways. The findings underscore the sensitivity of neutrophils and other hematopoietic lineages to perturbations in VPS45-mediated intracellular trafficking.
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