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

Sci Transl Med. 2016 Jul 13;8(347):347ra93. doi: 10.1126/scitranslmed.aaf6038.


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.

MeSH terms

  • Animals
  • Autoimmune Diseases / etiology*
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / metabolism
  • Autoimmunity / genetics
  • Autoimmunity / physiology
  • C9orf72 Protein / genetics*
  • CRISPR-Cas Systems / genetics
  • CRISPR-Cas Systems / physiology
  • Cytokines / metabolism
  • Leukemia / genetics
  • Leukemia / metabolism
  • Mice
  • Mutation / genetics
  • Splenomegaly / genetics
  • Splenomegaly / immunology
  • Thrombocytopenia / genetics
  • Thrombocytopenia / immunology


  • C9orf72 Protein
  • C9orf72 protein, mouse
  • Cytokines