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New immune disease cripples white cells

Written by | 1 Jul 2013 | All Medical News

A newly-described immunodeficiency syndrome of neutrophil defects, bone marrow fibrosis, nephromegaly, and life-threatening infections arises from a genetic mutation that impairs movement of proteins within cells, researchers found.

All seven affected children studied had homozygous mutations in VPS45, which encodes for a protein that regulates intracellular traffic of proteins through the endosomal system, Raz Somech, MD, PhD, of Israel’s Tel Aviv University, and colleagues reported online in the New England Journal of Medicine.

Putting normal VPS45 genetic material into patient cells ex vivo fixed the migration defect and cut down on neutrophil apoptosis.

“VPS45 deficiency should be considered in patients with neutropenia, bone marrow fibrosis, nephromegaly, migration defects, and severe bacterial and fungal infections,” the group wrote.

While the disorder is rare, the findings may have some broader implications by revealing more about the inner workings of the immune system, Somech and colleagues suggested.

Neutrophils play a particularly important role in fighting bacterial and fungal infections, in part by secreting proteins stored in specialized vesicles and fusing membrane compartments to kill ingested microbes.

A variety of other immunodeficiencies involving defective neutrophils have been described, with a range of mechanisms.

“The cellular defects in this new disease suggest that other immunodeficiency disorders may also result from impaired vesicle trafficking,” Somech’s group noted.

They studied seven children from five Palestinian families of common ancestry who presented in infancy with poor weight gain, enlarged livers and spleens, and severe infections or deep-seated abscesses.

The children also had neutropenia that didn’t respond to high-dose recombinant granulocyte colony-stimulating factor and bone marrow fibrosis.

Two siblings in one of the families also had delayed neurologic development, hearing loss, and cortical blindness, but it wasn’t clear whether those problems related to the VPS45 mutation or some other genetic abnormality.

Two of the children died from infection after failed hematopoietic stem-cell transplantation; three died before the procedure could be done.

Parents and unaffected siblings were healthy with normal blood counts and neutrophil function.

A search for the causative gene using homozygosity mapping with 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, and measurements of apoptosis turned up the following:

  • Homozygous mutation on VPS45 in Thr224Asn or Glu238Lys
  • Reduced levels of VPS45 protein and its binding partners rabenosyn-5 and syntaxin-16
  • Lower β1 integrin levels on the surface of VPS45-deficient neutrophils and fibroblasts
  • Impaired motility and increased apoptosis in VPS45-deficient fibroblasts

The mutations weren’t found in 250 ethnically-matched controls or in normal genome and exome databases.

“The absence of dysmorphic features such as albinism or short stature distinguishes this syndrome from other known syndromes associated with neutropenia, such as the Chédiak–Higashi syndrome, Griscelli’s syndrome type 2, the Hermansky-Pudlak syndrome type 2, and p14 deficiency,” the researchers noted.

The study was supported by the National Human Genome Research Institute, an advanced grant (EXPLORE) from 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 reported grants from the Israeli Ministry of Health, Israeli Science Foundation, and Jeffrey Modell Foundation.

Reference:  Vilboux T, et al “A congenital neutrophil defect syndrome associated with mutations in VPS45” N Engl J Med 2013; DOI: 10.1056/NEJMoa1301296.

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