title: JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.
abstract: The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils.
authors.affiliation: 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [2] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Järvinen
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Salzer
authors.affiliation: Department of Pediatrics, 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, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mönch
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Garncarz
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Antonopoulos
authors.affiliation: Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Haslam
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Schieck
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchałka
authors.affiliation: 1] Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. [2] Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Diestelhorst
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Giridharan
authors.initials: G
authors.lastname: Appaswamy
authors.affiliation: Department of Hematology, Hospital R Debré, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lescoeur
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giambruno
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Bigenzahn
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Cecilia Domínguez
authors.initials: CD
authors.lastname: Conde
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.affiliation: Department of Cell Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Brandes
authors.affiliation: Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Roya
authors.initials: R
authors.lastname: Sherkat
authors.affiliation: Department of Pediatrics, Hospital of the Free University of Brussels, Brussels, Belgium.
authors.forename: Jutte
authors.initials: J
authors.lastname: van der Werff Ten Bosch
authors.affiliation: Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.affiliation: Division of Pediatrics and Immunology, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.affiliation: Genetics Department, AP-HP Pitié-Salpêtrière Hospital, Pierre and Marie Curie University, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Giulio
authors.identifier: 0000000205701768
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: von Blume
authors.affiliation: Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Dell
authors.affiliation: Neutropenia Registry, Reference Center for Hereditary Immunodeficiencies, Pediatric Hematology, AP-HP, Armand Trousseau Children's Hospital, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Donadieu
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000080984:Congenital Bone Marrow Failure Syndromes; D005260:Female; D006031:Glycosylation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism*; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C000594489:JAGN1 protein, human; D008565:Membrane Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor