SNAREing a new cause of neutropenia.

Severe congenital neutropenia (SCN) is characterized by severe isolated neutropenia from birth, recurring bacterial infections, and a marked propensity to develop a myelodysplastic syndrome or acute myeloid leukemia. SCN is a genetically heterogeneous disorder (see figure). Mutations of ELANE encoding neutrophil elastase (NE) account for ;60% of cases (all in autosomal dominant or sporadic SCN). Mutations of HAX1, G6PC3, GFI1, G6PT1, WAS, and CSF3R collectively account for approximately 10% to 20% of cases of SCN. Thus, the genetic basis for approximately 20% to 30% of cases of SCN is unknown. Of note, all the aforementioned gene mutations are thought to induce neutropenia through the disruption of granulopoiesis. In contrast, mutations of CXCR4 or CXCR2 result in neutropenia through impaired release of neutrophils from the bone marrow to blood. Stepensky et al describe 5 patients from 2 unrelated families with consanguineous marriages who presented with recurrent infection in the first year of life. They were found to have severe persistent neutropenia, progressive transfusion-dependent anemia, and variable thrombocytopenia. They also presented with features of myelofibrosis, including increased bone marrow fibrosis, teardrop red blood cells, and mild splenomegaly. Unlike most cases of SCN, maturation arrest in the myeloid series was not observed and the patients did not respond to granulocyte colony-stimulating factor. A single patient underwent allogeneic stem cell transplantation with correction of the hematopoietic defects, suggesting that VPS45 mutations act in a cell intrinsic fashion to disrupt hematopoiesis. Using a combination of linkage analysis and whole exome sequencing, Stepensky et al identified homozygous Thr224Asn mutations of VPS45 in all 4 affected patients with available DNA. This mutation was not observed in nonaffected family members or in a large number of healthy individuals. VPS45 encodes for a protein that contributes to the assembly of the SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor) complex. The SNARE complex plays an essential role in the trafficking of proteins to lysosomes and other endosomes in the cell. Prior studies in yeast have established that loss of VPS45 results in the degradation of key components of the SNARE complex and defective transport of proteins from the trans–Golgi network to endosomes. Stepensky et al provide strong evidence that the Thr224Asn VPS45 mutation Genetic causes of congenital neutropenia. Neutrophilic granulopoiesis occurs primarily in the bone marrow through the stepwise maturation of myeloid progenitors (eg, colony-forming unit–granulocyte, monocyte, or CFU-GM) to promyelocytes (pro), myelocytes, and finally mature neutrophils (PMNs). PMNs are then released into the blood in a regulated fashion. Gene mutations associated with SCN are shown in the left panel. These mutations are typically associated with isolated severe neutropenia and a block in granulocytic differentiation. In contrast, mutations of CXCR4 and CXCR2 cause neutropenia by inhibiting neutrophil release from the bone marrow. Stepensky et al describe a new syndrome characterized by neutropenia, myelofibrosis, and impaired protein trafficking to endosomes that is due to VPS45 mutations. Mutations of VPS45 can be added to the list of gene mutations that affect protein trafficking to endosomes and are associated with congenital neutropenia (middle panel). Professional illustration by Marie Dauenheimer.