TY - JOUR
T1 - Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease
AU - Burberry, Aaron
AU - Suzuki, Naoki
AU - Wang, Jin Yuan
AU - Moccia, Rob
AU - Mordes, Daniel A.
AU - Stewart, Morag H.
AU - Suzuki-Uematsu, Satomi
AU - Ghosh, Sulagna
AU - Singh, Ajay
AU - Merkle, Florian T.
AU - Koszka, Kathryn
AU - Li, Quan Zhen
AU - Zon, Leonard
AU - Rossi, Derrick J.
AU - Trowbridge, Jennifer J.
AU - Notarangelo, Luigi D.
AU - Eggan, Kevin
N1 - Funding Information:
K.E. was supported by the Howard Hughes Medical Institute, p2ALS, Target ALS, and NIH5R01NS089742. F.T.M. was supported by the NIH (5K99NS083713), the Wellcome Trust, the Academy of Medical Sciences, and the Medical Research Council (MR/P501967/1).
PY - 2016/7/13
Y1 - 2016/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978287610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978287610&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaf6038
DO - 10.1126/scitranslmed.aaf6038
M3 - Article
C2 - 27412785
AN - SCOPUS:84978287610
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 347
M1 - 6038
ER -