Severe congenital neutropenia: genetics and pathogenesis

Trans Am Clin Climatol Assoc. 2006:117:13-31; discussion 31-2.


Severe congenital neutropenia (SCN) is a rare hematological disease characterized by a selective decrease in circulating neutrophils, bone marrow maturation arrest at the promyelocyte stage, and occurrence of infections. Studies of SCN patients revealed impaired proliferative characteristics and accelerated apoptosis of bone marrow progenitor cells. Sequencing analysis indicated a heterozygous deletion or substitution mutations in the neutrophil elastase (NE gene) in many patients. Expression of NE mutants but not normal NE accelerated apoptosis of human HL-60 progenitor cells similar to that seen with actual patient cells. Our data indicate that impaired survival of bone marrow myeloid progenitor cells arises from expression of mutant NE which contributes to neutropenia in SCN. In an unusual clinical set of studies during which SCN developed in five children from four families impregnated by the same sperm donor, we identified the responsible donor by employing genomic DNA studies.

MeSH terms

  • Apoptosis / genetics
  • Case-Control Studies
  • Female
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • HL-60 Cells
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / genetics
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / metabolism
  • Male
  • Mutation
  • Neutropenia / congenital*
  • Neutropenia / etiology
  • Neutropenia / genetics*
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transfection


  • Receptors, Granulocyte Colony-Stimulating Factor
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • Leukocyte Elastase