title: Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.
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.
authors.affiliation: 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.
authors.forename: Aaron
authors.initials: A
authors.lastname: Burberry
authors.affiliation: 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Rob
authors.initials: R
authors.lastname: Moccia
authors.affiliation: 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.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mordes
authors.affiliation: 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.
authors.forename: Morag H
authors.initials: MH
authors.lastname: Stewart
authors.affiliation: 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.
authors.forename: Satomi
authors.initials: S
authors.lastname: Suzuki-Uematsu
authors.affiliation: 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.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Florian T
authors.initials: FT
authors.lastname: Merkle
authors.affiliation: 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.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Koszka
authors.affiliation: Departments of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Zon
authors.affiliation: 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.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Rossi
authors.affiliation: The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Trowbridge
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA. Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000502:physiology; D000073885:C9orf72 Protein / Q000235:genetics*; D064113:CRISPR-Cas Systems / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D013921:Thrombocytopenia / Q000235:genetics / Q000276:immunology
chemical_list: D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D016207:Cytokines