Identification of disease causing mutations in a new congenital neutrophil defect syndrome. T. Vilboux1, A. Lev2, M. C. Malicdan1, S. Amos2, R. Sood3, Y. Anikster4, C. Klein5, W. A. Gahl1, R. Somech6 1) Medical Genetics Branch, NHGRI, NIH, Bethesda, MD; 2) The Claim Sheba Medical Center, Sheba Cancer Research Center, Pediatric Immunology, JMF center for PID; 3) Zebrafish Core Genetics and Molecular Biology Branch; 4) Edmond and Lily Safra Children's Hospital Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Metabolic Disease Unit; 5) Ludwig Maximilians University Munich, Pediatrics; 6) Edmond and Lily Safra Childrens Hospital, Sheba Medical Center, Tel Hashomer. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Israel, Pediatrics B.

   Neutrophils are the predominant phagocytes that protect the host against bacterial and fungal infections. The important role of neutrophils in innate immunity is underscored by the multiple congenital defects that lead to severe infections. These disorders are characterized by genetic abnormalities that alter the neutrophil number and/or their function. To identify the causative gene, we combined the data of single-nucleotide polymorphism arrays of multiple families and a single exome. Functional studies were performed on patient neutrophils and fibroblasts, and on a zebrafish model. We describe seven patients from five families, who displayed a unique constellation of severe neutrophil dysfunction, bone marrow fibrosis and nephromegaly. From our analysis, this new immunodeficiency is associated with biallelic mutations in the VPS45 gene, encoding a protein that regulates membrane traffic through the endosomal system. Two distinct homozygous VPS45 mutations were identified in patients from different ethnic origins. Functional studies showed that VPS45 mutations affected protein recycling, altered cell migration and neutrophil maturation, and induced cell apoptosis. Both the migration defect and the enhanced apoptosis were rescued by expressing the wild-type VPS45 in patient cells. Neutrophil defect was recapitulated in a zebrafish model. Mutations in VPS45 underlie a new immunodeficiency syndrome with bone marrow fibrosis and severe neutropenia. This can pave the way into understanding and finding more immunodeficiencies that are associated with endocytosis or phagosome defect.

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