A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis

Pediatr Blood Cancer. 2017 Sep;64(9). doi: 10.1002/pbc.26571. Epub 2017 Apr 28.

Abstract

VPS45-associated severe congenital neutropenia (SCN) is a rare disorder characterized by life-threating infections, neutropenia, neutrophil and platelet dysfunction, poor response to filgrastim, and myelofibrosis with extramedullary hematopoiesis. We present a patient with SCN due to a homozygous c.1403C>T (p.P468L) mutation in VPS45, critical regulator of SNARE-dependent membrane fusion. Structural modeling indicates that P468, like the T224 and E238 residues affected by previously reported mutations, cluster in a VPS45 "hinge" region, indicating its critical role in membrane fusion and VPS45-associated SCN. Bone marrow transplantation, complicated by early graft failure rescued with stem cell boost, led to resolution of the hematopoietic phenotype.

Keywords: SNARE; VPS45; primary myelofibrosis of infancy; severe congenital neutropenia.

Publication types

  • Case Reports

MeSH terms

  • Congenital Bone Marrow Failure Syndromes
  • Female
  • Homozygote
  • Humans
  • Infant, Newborn
  • Mutation
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Primary Myelofibrosis / genetics*
  • Vesicular Transport Proteins / genetics*

Substances

  • VPS45 protein, human
  • Vesicular Transport Proteins

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3