Inherited biallelic CSF3Rmutations in severe congenital neutropenia

• Published in: Blood Vol. 123; no. 24; pp. 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: Journal Article
• Language: English
• Published: Elsevier Inc 12.06.2014
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-11-535419

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. •Biallelic mutations in CSF3Rmust be considered as a novel genetic subtype in patients with congenital neutropenia.•The p.Arg308Cys mutation in CSF3Rleads to altered G-CSF receptor glycosylation and surface expression and abrogated downstream signaling.