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
  • 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.