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Sci Transl Med. 2016 Jul 13;8(347):347ra93. doi: 10.1126/scitranslmed.aaf6038.

Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.

Author information

1
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
3
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
4
Departments of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Harvard Medical School, Boston, MA 02115, USA.
6
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA.
7
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
8
Harvard Medical School, Boston, MA 02115, USA. Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
9
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. eggan@mcb.harvard.edu.

Abstract

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity.

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PMID:
27412785
PMCID:
PMC5024536
DOI:
10.1126/scitranslmed.aaf6038
[Indexed for MEDLINE]
Free PMC Article

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