Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease
- 13 July 2016
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 8 (347), 347ra93
- https://doi.org/10.1126/scitranslmed.aaf6038
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.Keywords
Funding Information
- Howard Hughes Medical Institute (NIH5R01NS089742)
- NIH (5K99NS083713)
- Wellcome Trust
- Academy of Medical Sciences
- Medical Research Council (MR/P501967/1)
This publication has 46 references indexed in Scilit:
- Hepatic Manifestations in Hematological DisordersInternational Journal of Hepatology, 2013
- The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFsBioinformatics, 2013
- Regulatory T‐lymphocytes mediate amyotrophic lateral sclerosis progression and survivalEMBO Molecular Medicine, 2012
- Amyotrophic lateral sclerosisCurrent Opinion in Neurology, 2012
- Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort studyThe Lancet Neurology, 2012
- Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALSNeuron, 2011
- Autoimmunity in Amyotrophic Lateral Sclerosis: Past and PresentNeurology Research International, 2011
- T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALSProceedings of the National Academy of Sciences of the United States of America, 2008
- The Immunological Genome Project: networks of gene expression in immune cellsNature Immunology, 2008
- Control of V(D)J Recombinational Accessibility of the Dβ1 Gene Segment at the TCRβ Locus by a Germline PromoterImmunity, 1999