1. Inherited biallelic CSF3R mutations in severe congenital neutropenia
- Author
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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, and Hematology
- Subjects
Male ,Neutropenia ,Myeloid ,Immunology ,Mutation, Missense ,Granulocyte ,Biology ,Compound heterozygosity ,medicine.disease_cause ,Biochemistry ,Granulopoiesis ,Phagocytes, Granulocytes, and Myelopoiesis ,Receptors, Colony-Stimulating Factor ,medicine ,Congenital Bone Marrow Failure Syndromes ,Humans ,Missense mutation ,Congenital Neutropenia ,Mutation ,Cell Biology ,Hematology ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Female - 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.
- Published
- 2014
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