Inherited biallelic CSF3R mutations in severe congenital neutropenia

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 CS...

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Bibliographic Details
Published in:Blood 2014-06, Vol.123 (24), p.3811-3817
Main Authors: Triot, Alexa, Järvinen, Päivi M, Arostegui, Juan I, Murugan, Dhaarini, Kohistani, Naschla, Dapena Díaz, José Luis, Racek, Tomas, Puchałka, Jacek, Gertz, E Michael, Schäffer, Alejandro A, Kotlarz, Daniel, Pfeifer, Dietmar, Díaz de Heredia Rubio, Cristina, Ozdemir, Mehmet Akif, Patiroglu, Turkan, Karakukcu, Musa, Sánchez de Toledo Codina, José, Yagüe, Jordi, Touw, Ivo P, Unal, Ekrem, Klein, Christoph
Format: Article
Language:English
Subjects:
Base Sequence
Child
Child, Preschool
Congenital Bone Marrow Failure Syndromes
Female
HeLa Cells
Homozygote
Humans
Infant
Infant, Newborn
Male
Models, Molecular
Mutation, Missense
Neutropenia - congenital
Neutropenia - genetics
Pedigree
Phagocytes, Granulocytes, and Myelopoiesis
Receptors, Colony-Stimulating Factor - chemistry
Receptors, Colony-Stimulating Factor - genetics
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Summary: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 frameshifts 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-11-535419