Congenital immunodeficiencies comprise a group of disorders characterized by an abnormal immune system. The body’s ability to fight infections is impaired and infections can have life-threatening consequences for those affected. Analysis of patients with a disease characterized by an inherited lack of neutrophil granulocytes termed severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling differentiation, maintenance, and decay of neutrophils. The team of CeMM Principal Investigator Kaan Boztug in collaboration with the group of Christoph Klein, Director of the Dr. Von Hauner Children’s Hospital Munich, identified mutations in the gene JAGN1 as a novel subtype of SCN in 14 patients bearing 9 distinct JAGN1 mutations. JAGN1 deficiency accounts for approximately 10% SCN for which the underlying genetic defect had previously been unknown. The researchers could show that JAGN1 mutations lead to aberrant function of the endoplasmic reticulum, defective protein glycosylation and increased neutrophil apoptosis. SCN patients are usually treated with the cytokine G-CSF, however for JAGN1-deficient patients the treatment response was unsatisfactory. In a second study IMBA Director Josef Penninger and his team generated Jagn1 knock-out mice and could show that GM-CSF, but not G-CSF, treatment rescues the defects of JAGN1-deficient neutrophils in mice.

Kaan Boztug, first author of one of the studies, identified the first patients with JAGN1 mutations: “The discovery of the JAGN1 deficiency illustrates that inborn errors of immunity can be caused by mutations in genes that were previously not even known to play a role in the immune system. It would be a wonderful result of this CeMM-IMBA-Munich collaboration if treatment with GM-CSF also works for human patients – this will now be assessed in further clinical studies. This is also a perfect example that not only new drugs lead to better therapies. An enhanced molecular understanding of diseases may enable targeted use of existing drugs and can thus fulfill the promise of patient-oriented medicine."

The findings of both studies have been published on August 17, 2014, in the journal Nature Genetics:

Boztug, K. et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. (2014).

Wirnsberger, G. et al. Jagunal-homolog 1 is a critical regulator of neutrophil function in fungal host defense. Nat Genet. (2014).