A molecular approach to the study of severe congenital neutropenia

Starting date
October 1, 2008
Duration (months)
Managers or local contacts
Cellini Barbara
Congenital neutropenia, Mutations, Protein folding, Pathogenesis, Molecular pathology

Severe congenital neutropenia (SCN) is an inherited disorder of granulopoiesis that, in 50% of cases, results from mutations in the gene encoding human neutrophil elastase (HNE). Recent studies have suggested that SCN is a protein misfolding disease, in that most pathogenic aminoacid substitutions prevent correct HNE folding.
The main objective of the proposed research project is a deep understanding of the pathogenesis of SCN by a multidisciplinary three-phase strategy:
  • phase 1: in vitro biochemical studies on purified wild-type and mutant HNE in order to i)elucidate how pathogenic mutations affect protein folding and ii)identify ligands acting as chaperones able to promote the correct folding of conformationally-defective variants;
  • phase 2: test of the effects of chaperones molecules on cell lines expressing mutant HNE in order to select molecules that prevent cellular stress without concomitant toxic effects;
  • phase 3: test of the best candidates selected on phase 2 to treat granulocytes isolated from SCN patients in order to verify their potential application as therapeutic agents.


Funds: assigned and managed by the department

Project participants

Antonio Lorenzetto
Riccardo Montioli
Temporary Assistant Professor


Research facilities