JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

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

Kaan Boztug ¹, Päivi M Järvinen ², Elisabeth Salzer ³, Tomas Racek ², Sebastian Mönch ², Wojciech Garncarz ³, E Michael Gertz ⁴, Alejandro A Schäffer ⁴, Aristotelis Antonopoulos ⁵, Stuart M Haslam ⁵, Lena Schieck ⁶, Jacek Puchałka ², Jana Diestelhorst ⁷, Giridharan Appaswamy ⁶, Brigitte Lescoeur ⁸, Roberto Giambruno ³, Johannes W Bigenzahn ³, Ulrich Elling ⁹, Dietmar Pfeifer ¹⁰, Cecilia Domínguez Conde ³, Michael H Albert ², Karl Welte ⁶, Gudrun Brandes ¹¹, Roya Sherkat ¹², Jutte van der Werff Ten Bosch ¹³, Nima Rezaei ¹⁴, Amos Etzioni ¹⁵, Christine Bellanné-Chantelot ¹⁶, Giulio Superti-Furga ³, Josef M Penninger ⁹, Keiryn L Bennett ³, Julia von Blume ¹⁷, Anne Dell ⁵, Jean Donadieu ¹⁸, Christoph Klein ²

Affiliations

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.

PMID: 25129144 DOI: 10.1038/ng.3069

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.

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