title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
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.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Alexa
authors.initials: A
authors.lastname: Triot
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Järvinen
authors.affiliation: Immunology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Juan I
authors.initials: JI
authors.lastname: Arostegui
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Dhaarini
authors.initials: D
authors.lastname: Murugan
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Naschla
authors.initials: N
authors.lastname: Kohistani
authors.affiliation: Department of Pediatric Oncology-Hematology, Maternal-Infant Hospital Vall d'Hebron, Barcelona, Spain;
authors.forename: José Luis
authors.initials: JL
authors.lastname: Dapena Díaz
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Tomas
authors.initials: T
authors.lastname: Racek
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchałka
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD;
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD;
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Pediatric Oncology-Hematology, Maternal-Infant Hospital Vall d'Hebron, Barcelona, Spain;
authors.forename: Cristina
authors.initials: C
authors.lastname: Díaz de Heredia Rubio
authors.affiliation: Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; and.
authors.forename: Mehmet Akif
authors.initials: MA
authors.lastname: Ozdemir
authors.affiliation: Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; and.
authors.forename: Turkan
authors.initials: T
authors.lastname: Patiroglu
authors.affiliation: Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; and.
authors.forename: Musa
authors.initials: M
authors.lastname: Karakukcu
authors.affiliation: Department of Pediatric Oncology-Hematology, Maternal-Infant Hospital Vall d'Hebron, Barcelona, Spain;
authors.forename: José
authors.initials: J
authors.lastname: Sánchez de Toledo Codina
authors.affiliation: Immunology Department, Hospital Clínic, Barcelona, Spain;
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.affiliation: Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; and.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Unal
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D000080984:Congenital Bone Marrow Failure Syndromes; D005260:Female; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D016184:Receptors, Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics*
chemical_list: C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor
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