Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 8, Issue 347, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaf6038
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Funding
- Howard Hughes Medical Institute
- p2ALS
- Target ALS
- NIH [5K99NS083713]
- Wellcome Trust
- Academy of Medical Sciences
- Medical Research Council [MR/P501967/1]
- [NIH5R01NS089742]
- Medical Research Council [MR/P501967/1] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15H05667] Funding Source: KAKEN
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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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