JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

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

doi:10.1038/ng.3069

JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

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

Authors

Kaan Boztug¹, Päivi M Järvinen², Elisabeth Salzer³, Tomas Racek², Sebastian Mönch², Wojciech Garncarz³, E Michael Gertz⁴, Alejandro A Schäffer⁴, Aristotelis Antonopoulos⁵, Stuart M Haslam⁵, Lena Schieck⁶, Jacek Puchałka², Jana Diestelhorst⁷, Giridharan Appaswamy⁶, Brigitte Lescoeur⁸, Roberto Giambruno³, Johannes W Bigenzahn³, Ulrich Elling⁹, Dietmar Pfeifer¹⁰, Cecilia Domínguez Conde³, Michael H Albert², Karl Welte⁶, Gudrun Brandes¹¹, Roya Sherkat¹², Jutte van der Werff Ten Bosch¹³, Nima Rezaei¹⁴, Amos Etzioni¹⁵, Christine Bellanné-Chantelot¹⁶, Giulio Superti-Furga³, Josef M Penninger⁹, Keiryn L Bennett³, Julia von Blume¹⁷, Anne Dell⁵, Jean Donadieu¹⁸, Christoph Klein²

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
PMCID: PMC4829076
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Apoptosis / genetics
Cell Differentiation / genetics
Cell Survival / genetics
Child
Child, Preschool
Congenital Bone Marrow Failure Syndromes
Female
Glycosylation
Homeostasis / genetics
Humans
Infant
Infant, Newborn
Male
Membrane Proteins / deficiency*
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mutation
Myeloid Cells / metabolism*
Neutropenia / congenital*
Neutropenia / genetics
Neutropenia / metabolism
Neutropenia / pathology
Neutrophils / metabolism
Receptors, Granulocyte Colony-Stimulating Factor / genetics
Receptors, Granulocyte Colony-Stimulating Factor / metabolism
Signal Transduction
Young Adult

JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

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