A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis
Department of Biochemistry and Molecular Pharmacology; Department of Pediatrics, Division of Hematology/Oncology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Hematology | Hemic and Lymphatic Diseases | Oncology | Pediatrics
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.
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Citation: Pediatr Blood Cancer. 2017 Apr 28. doi: 10.1002/pbc.26571. Link to article on publisher's site
Shah, Rikin K.; Munson, Mary; Wierenga, Klaas J.; Pokala, Hanumantha R.; Newburger, Peter E.; and Crawford, David, "A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis" (2017). Pediatric Publications and Presentations. 119.