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

Rikin K. Shah, Mary Munson, Klaas J. Wierenga, Hanumantha R. Pokala, Peter E. Newburger, David Crawford

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Article numbere26571
JournalPediatric Blood and Cancer
Volume64
Issue number9
DOIs
StatePublished - Sep 2017
Externally publishedYes

Keywords

  • primary myelofibrosis of infancy
  • severe congenital neutropenia
  • SNARE
  • VPS45

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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