Hereditary neutropenia: dogs explain human neutrophil elastase mutations

Trends Mol Med. 2004 Apr;10(4):163-70. doi: 10.1016/j.molmed.2004.02.002.


Mutations in ELA2, the gene encoding neutrophil elastase (NE), cause the human diseases cyclic neutropenia (CN) and severe congenital neutropenia (SCN). Numerous mutations are known, but their lack of consistent biochemical effect has proven puzzling. The recent finding that mutation of AP3B1, which encodes the beta subunit of adaptor protein complex 3 (AP3), is the cause of canine CN suggests a model for the molecular basis of hereditary neutropenias, involving the mistrafficking of NE: AP3 recognizes NE as a cargo protein, and their interaction implies that NE is a transmembrane protein. Computerized algorithms predict two NE transmembrane domains. Most CN mutations fall within predicted transmembrane domains and lead to excessive deposition of NE in granules, whereas SCN mutations usually disrupt the AP3 recognition sequence, resulting in excessive transport to the plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits
  • Animals
  • Cell Membrane / metabolism
  • Disease Models, Animal
  • Dogs
  • Humans
  • Leukocyte Elastase / genetics*
  • Leukocyte Elastase / metabolism*
  • Membrane Transport Proteins / genetics
  • Models, Biological
  • Models, Molecular
  • Mutation*
  • Neutropenia / genetics*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Protein Transport
  • Time Factors


  • AP3B1 protein, human
  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits
  • Membrane Transport Proteins
  • Leukocyte Elastase