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; Senior Scholars Program; School of Medicine
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.
DOI of Published Version
Pediatr Blood Cancer. 2017 Apr 28. doi: 10.1002/pbc.26571. Link to article on publisher's site
Pediatric blood and cancer
Shah RK, Munson M, Wierenga KJ, Pokala HR, Newburger PE, Crawford D. (2017). A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis. Pediatric Publications. https://doi.org/10.1002/pbc.26571. Retrieved from https://escholarship.umassmed.edu/peds_pp/119