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Nat Genet. 2014 Sep;46(9):1021-7. doi: 10.1038/ng.3069. Epub 2014 Aug 17.

JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.

Author information

1
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.
2
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
3
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
4
Computational Biology Branch, National Center for Biotechnology Information, US National Institutes of Health, Bethesda, Maryland, USA.
5
Department of Life Sciences, Imperial College London, London, UK.
6
Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
7
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.
8
Department of Hematology, Hospital R Debré, Paris, France.
9
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
10
Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany.
11
Department of Cell Biology, Hannover Medical School, Hannover, Germany.
12
Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
13
Department of Pediatrics, Hospital of the Free University of Brussels, Brussels, Belgium.
14
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
15
Division of Pediatrics and Immunology, Rappaport School of Medicine, Technion, Haifa, Israel.
16
Genetics Department, AP-HP Pitié-Salpêtrière Hospital, Pierre and Marie Curie University, Paris, France.
17
Max Planck Institute of Biochemistry, Martinsried, Germany.
18
Neutropenia Registry, Reference Center for Hereditary Immunodeficiencies, Pediatric Hematology, AP-HP, Armand Trousseau Children's Hospital, Paris, France.

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.

PMID:
25129144
PMCID:
PMC4829076
DOI:
10.1038/ng.3069
[Indexed for MEDLINE]
Free PMC Article

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