2. Academic Validation
  3. Inherited biallelic CSF3R mutations in severe congenital neutropenia

Inherited biallelic CSF3R mutations in severe congenital neutropenia

  • Blood. 2014 Jun 12;123(24):3811-7. doi: 10.1182/blood-2013-11-535419.
Alexa Triot 1,  Päivi M Järvinen 1,  Juan I Arostegui 2,  Dhaarini Murugan 1,  Naschla Kohistani 1,  José Luis Dapena Díaz 3,  Tomas Racek 1,  Jacek Puchałka 1,  E Michael Gertz 4,  Alejandro A Schäffer 4,  Daniel Kotlarz 1,  Dietmar Pfeifer 5,  Cristina Díaz de Heredia Rubio 3,  Mehmet Akif Ozdemir 6,  Turkan Patiroglu 6,  Musa Karakukcu 6,  José Sánchez de Toledo Codina 3,  Jordi Yagüe 2,  Ivo P Touw 7,  Ekrem Unal 6,  Christoph Klein 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
  • 2 Immunology Department, Hospital Clínic, Barcelona, Spain;
  • 3 Department of Pediatric Oncology-Hematology, Maternal-Infant Hospital Vall d'Hebron, Barcelona, Spain;
  • 4 Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD;
  • 5 Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany;
  • 6 Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; and.
  • 7 Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
PMID: 24753537 DOI: 10.1182/blood-2013-11-535419
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 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.

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