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VPS45 mutation associated with new immunodeficiency syndrome in children
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Researchers have identified an association between defective endosomal intracellular protein trafficking — due to biallelic mutations in VPS45 — and a new immunodeficiency syndrome that impairs neutrophil function in children.
“Clinical observation is the first and most important step in discovering new monogenetic diseases, especially in the field of primary immunodeficiency,” Raz Somech, MD, PhD, of the Edmond and Lily Safra Children’s Hospital at Sheba Medical Center in Israel, told HemOnc Today. “This should be followed by a thorough investigation using advanced genetic and molecular assays. These diseases illuminate basic mechanisms of immune protection.”
Raz Somech
Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders present a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis and innate immunity, the researchers wrote.
The study included seven children from five families from two different ethnic origins. All children had neutropenia, neutrophil dysfunction, bone marrow fibrosis and nephromegaly.
The investigators used homozygosity mapping followed by whole-exome sequencing to identify a causative gene.
Results indicated that the seven children had two different homozygous mutations in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system.
The protein levels of VPS45 and its binding partners, rabenosyn-5 and syntaxin-16, were reduced. The researchers also found that beta-1 integrin levels were reduced on the surface of VPS45-deficient neutrophils and fibroblasts.
Impaired mobility and increased apoptosis were characteristics of VPS45-deficient fibroblasts. The migration defect was corrected and apoptosis decreased with transfection of patient cells with nonmutated VPS45. The disease phenotype was recapitulated in a zebrafish model with reduced VPS45 levels.
“VPS45 deficiency should be considered in patients with neutropenia, bone marrow fibrosis, nephromegaly, migration defects and severe bacterial and fungal infections,” the researchers wrote. “The cellular defects in this new disease suggest that other immunodeficiency disorders may also result from impaired vesicle trafficking.”
Raz Somech, MD, PhD, can be reached at raz.somech@sheba.health.gov.il.
Disclosure: This study was funded by the National Human Genome Research Institute’s Intramural Research Program, the European Research Council, the Gottfried-Wilhelm-Leibniz Program of the Deutsche Forschungsgemeinschaft, the Care-for-Rare Foundation, and the German Network on Primary Immunodeficiency Diseases. Somech also reports grants from the Jeffrey Modell Foundation, the Israeli Science Foundation, and the Chief Scientist Office of the Israeli Ministry of Health.
Perspective
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Laurence A. Boxer, MD
An international group of investigators described a novel genetic cause for congenital neutropenia. Clinically, they identified seven patients from five families found to have neutropenia, bone marrow fibrosis, nephromegaly, neutrophil and fibroblast motility defects, predisposing patients to bacterial and fungal infections. Accompanying the cellular defects, the children all had developmental delay. The neutrophil dysfunction and neurologic abnormalities are reminiscent of other congenital neutropenias arising from intracellular transport defects. The authors pursued this line of thinking and used state-of-the-art homozygosity mapping and identified a mutation in VPS45.
VPS45 is a protein found on the membranes of intracellular vesicles derived from the Golgi apparatus or endoplasmic reticulum carrying key proteins vital to the plasma membrane. VPS45 is one of several proteins mediating fusion of intracellular vesicles to key receptors on the plasma membrane, thereby allowing the release of critical protein necessary for the function of cells. In this syndrome, the vital protein was beta-1 integrin, which mediates cell attachment and motility. The authors were able to reproduce the neutropenia in zebrafish embryos injected with the defective VPS45-specific mutation. Furthermore, the authors were able to correct fibroblast dysfunction by transfecting the defective fibroblasts with the non mutated gene, thereby providing a strategy for possible treatment in the future.
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