Inherited biallelic CSF3R mutations in severe congenital neutropenia

Blood. 2014 Jun 12;123(24):3811-7. doi: 10.1182/blood-2013-11-535419. Epub 2014 Apr 21.

Abstract

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Child
  • Child, Preschool
  • Congenital Bone Marrow Failure Syndromes
  • Female
  • HeLa Cells
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Models, Molecular
  • Mutation, Missense*
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Pedigree
  • Receptors, Colony-Stimulating Factor / chemistry
  • Receptors, Colony-Stimulating Factor / genetics*

Substances

  • CSF3R protein, human
  • Receptors, Colony-Stimulating Factor

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3

Associated data

  • PDB/2D9Q