A Variant of Congenital Neutropenia Is Caused by a 3′-UTR Mutation in the Gene Encoding the Endosomal Adaptor Protein p14 (MAPBPIP).

We have investigated the molecular etiology of autosomal recessive congenital neutropenia in a pedigree of 15 members with four affected children. Combining genome wide linkage analysis and a transcriptional profiling approach, we identified a homozygous mutation in the 3′-UTR of p14 (MAPBPIP), a recently identified adaptor molecule controlling late endosomal signaling by the MP1-MAPK complex. The mutation segregated with the disease, and neutrophils from all patients showed decreased RNA and protein levels of p14. To further assess the significance of this point mutation, we designed firefly luciferase reporter plasmids carrying either wildtype or mutated 3′-UTRs and cotransfected these constructs together with renilla luciferase expression plasmids into CHO cells. The specific luciferase activity was consistently decreased in the mutated constructs, suggesting that the mutated 3′-UTR is associated with decreased RNA levels in a heterologous system. Mechanistically, we excluded aberrant splicing and aberrant polyadenylation as a cause for decreased RNA levels. However, an increased ratio of unprocessed to processed nuclear RNA in transfected cells suggests a defect in RNA processing. Decreased levels of p14 lead to an abnormal configuration of lysosomes in granulocytes as shown by transmission electron microscopy. Whereas phagocytosis capacity is normal, killing of pathogenic bacteria is reduced in p14-deficient granulocytes. This defect is reversed upon retroviral p14 gene transfer into hematopoietic stem cells and subsequent differentiation into neutrophils in vitro. In summary, we provide evidence that decreased levels of p14 cause neutropenia. Furthermore, our report extends the small list of hereditary diseases associated with 3′-UTR mutations.