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

Aaron Burberry, Naoki Suzuki, Jin Yuan Wang, Rob Moccia, Daniel A. Mordes, Morag H. Stewart, Satomi Suzuki-Uematsu, Sulagna Ghosh, Ajay Singh, Florian T. Merkle, Kathryn Koszka, Quan Zhen Li, Leonard Zon, Derrick J. Rossi, Jennifer J. Trowbridge, Luigi D. Notarangelo, Kevin Eggan

Research output: Contribution to journalArticlepeer-review

192 Citations (Scopus)


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.

Original languageEnglish
Article number6038
JournalScience Translational Medicine
Issue number347
Publication statusPublished - 2016 Jul 13


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