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Inherited biallelic CSF3R mutations in severe congenital neutropenia

Authors :
Jordi Yagüe
Dhaarini Murugan
José Sanchez de Toledo Codina
Christina Díaz de Heredia Rubio
Dietmar Pfeifer
Ivo P. Touw
Christoph Klein
Jacek Puchałka
Musa Karakukcu
Alexa Triot
Juan I. Aróstegui
Turkan Patiroglu
Jose Luis Dapena Díaz
Daniel Kotlarz
E. Michael Gertz
Päivi M Järvinen
Ekrem Unal
Alejandro A. Schäffer
Mehmet Akif Ozdemir
Tomas Racek
Naschla Kohistani
Hematology
Source :
Blood, Blood, 123(24), 3811-3817. American Society of Hematology
Publication Year :
2014
Publisher :
American Society of Hematology, 2014.

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 frame shifts 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.

Details

ISSN :
15280020 and 00064971
Volume :
123
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....645f076efa8d1947268a137c82181e1c
Full Text :
https://doi.org/10.1182/blood-2013-11-535419