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Published on: July 16, 2021
Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease
Aaron Burberry1, Naoki Suzuki1, Jin-Yuan Wang1
1Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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.
Insights
Mutations in C9ORF72 cause severe autoimmunity and death in mice by affecting the hematopoietic system. Restoring C9ORF72 function in bone marrow prevents these detrimental effects.
Area of Science:
- Genetics
- Immunology
- Neuroscience
Background:
- C9ORF72 mutations are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- The precise function of the C9ORF72 gene product is largely unknown.
- Understanding C9ORF72's role is crucial for neurodegenerative disease research.
Purpose of the Study:
- To investigate the in vivo function of C9ORF72.
- To determine the role of C9ORF72 in the hematopoietic system and autoimmunity.
Main Methods:
- Generation and analysis of mice with loss-of-function mutations in the C9ORF72 ortholog.
- Hematopoietic stem cell transplantation experiments (mutant to wild-type and vice versa).
- Assessment of clinical phenotypes, including splenomegaly, blood cell counts, cytokine expression, autoimmunity, and mortality.
Main Results:
- Mice with C9ORF72 loss-of-function mutations exhibited splenomegaly, neutrophilia, thrombocytopenia, elevated inflammatory cytokines, and severe autoimmunity.
- These mice experienced high mortality rates.
- Bone marrow transplantation studies confirmed the hematopoietic system's critical role, as mutant marrow caused disease in wild-type recipients, and wild-type marrow rescued mutant mice.
Conclusions:
- C9ORF72 plays a vital role in the hematopoietic system.
- The gene functions to restrict inflammation and prevent the development of autoimmunity.
- These findings offer insights into the pathogenesis of C9ORF72-associated neurodegenerative diseases.
