A Congenital Neutrophil Defect Syndrome Associated with Mutations inVPS45

Abstract

Background Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. Methods We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single-nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase–chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. Results All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the child's ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn-5 and syntaxin-16. The level of β1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. Conclusions Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (Funded by the National Human Genome Research Institute and others.)

Kruppel-like factor 4 regulates neutrophil activation

“…[1][2][3][4][5] Patients with congenital neutrophil deficiencies or neutropenia secondary to chemotherapy and other diseases suffer from life-threatening infections, underscoring the importance of neutrophils in health. [6][7][8] However, the transcriptional mechanisms that regulate neutrophil biology remain incompletely understood.…”

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

“…Possible causes of cytopenia in PIDs comprise cellular or humoral autoimmunity, immune dysregulation in form of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure and myelodysplasia, or secondary myelosuppression. In some patients, cytopenia may be detected as an incidental finding, whereas other patients may be severely ill. Because primary defects in the number or function of phagocytes are classified under their own group of PIDs, 3 the syndromes of severe congenital neutropenia (based on defects in ELANE, GFI1, HAX1, G6PC3, VPS45, and CSFR3 genes, or activating mutations in the Wiskott-Aldrich syndrome [WAS] gene) [4][5][6] and cytopenia-linked metabolic diseases are not included in this overview. Similarly, isolated lymphopenia syndromes are excluded if they present without neutropenia, anemia, or thrombocytopenia; also excluded are non-PID inherited bone marrow failure syndromes such as Fanconi anemia, congenital amegakaryocytic thrombocytopenia, bone marrow failure with radioulnar synostosis, and others (Table 1 and footnotes).…”

Inherited biallelic CSF3R mutations in severe congenital neutropenia

“…Autosomal-dominant, autosomal-recessive, X-linked, and sporadic forms have been described, with mutations in several genes, including ELANE, 1 GFI1, 2 HAX1, 3 G6PC3, 4 VPS45, 5 and WAS. 6 The genetic cause in many SCN patients remains unidentified.…”