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C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production and glomerulonephropathy in mice

2016; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/srep23204

2045-2322

Amanda Atanasio, Vilma Decman, Derek W. R. White, Meg Ferrell Ramos, Burcin Ikiz, Hoi-Ching Lee, Chia-Jen Siao, Susannah Brydges, Elizabeth LaRosa, Yu Bai, Wen Fury, Patricia Burfeind, Ralica Zamfirova, Gregg Warshaw, Jamie Orengo, A. Oyejide, Michael Fralish, Wojtek Auerbach, William Poueymirou, Jan Freudenberg, Guochun Gong, Brian Zambrowicz, David M. Valenzuela, George D. Yancopoulos, Andrew Murphy, Gavin Thurston, Ka‐Man Venus Lai,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.