Loss-of-function mutations in the <i>C9ORF72</i> mouse ortholog cause fatal autoimmune disease

TLDR

C9ORF72 mutations are implicated in amyotrophic lateral sclerosis and frontotemporal dementia, yet the gene’s biological role remains poorly understood. Loss‑of‑function mutations in the mouse C9ORF72 ortholog produce splenomegaly, neutrophilia, thrombocytopenia, increased inflammatory cytokines, severe autoimmunity, and high mortality, and bone‑marrow transplantation experiments demonstrate that C9ORF72 limits hematopoietic‑driven inflammation and autoimmunity.

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.