For those following the C9ORF72 story, this is a very interesting twist!
Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease
Aaron Burberry1,2, Naoki Suzuki1,2, Jin-Yuan Wang1,2, Rob Moccia1,2, Daniel A. Mordes1,2,3, Morag H. Stewart1,4, Satomi Suzuki-Uematsu1,2, Sulagna Ghosh1,2, Ajay Singh1,2, Florian T. Merkle1,2, Kathryn Koszka1,2, Quan-Zhen Li5, Leonard Zon1,6, Derrick J. Rossi1,4,6, Jennifer J. Trowbridge7, Luigi D. Notarangelo6,8 and Kevin Eggan1,2,*
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.