Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.
Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.
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DOI：
10.1126/scitranslmed.aaf6038
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发表时间：
2016-07-13
影响因子：
17.1
通讯作者：
Eggan K
中科院分区：
文献类型：
--
作者：
Burberry A;Suzuki N;Wang JY;Moccia R;Mordes DA;Stewart MH;Suzuki-Uematsu S;Ghosh S;Singh A;Merkle FT;Koszka K;Li QZ;Zon L;Rossi DJ;Trowbridge JJ;Notarangelo LD;Eggan K
C9ORF72突变在患有肌萎缩侧索硬化症和额颞叶痴呆的患者中被发现，但C9ORF72基因产物的功能仍然知之甚少。在这里，我们表明，小鼠窝藏功能丧失突变的直系同源的C9ORF72发展脾肿大，嗜中性粒细胞，血小板减少症，增加表达的炎性细胞因子，和严重的自身免疫，最终导致高死亡率。将突变骨髓移植到野生型受体中足以重现突变动物中观察到的表型，包括自身免疫和过早死亡。反过来，将野生型骨髓移植到突变小鼠中改善了它们的表型。我们得出的结论是，C9 ORF 72在造血系统中发挥着限制炎症和自身免疫发展的重要功能。
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. Here, 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 bone marrow into wildtype recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wildtype 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.
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DOI：
10.1126/science.aaf1064
发表时间：
2016-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Rourke JG;Bogdanik L;Yáñez A;Lall D;Wolf AJ;Muhammad AK;Ho R;Carmona S;Vit JP;Zarrow J;Kim KJ;Bell S;Harms MB;Miller TM;Dangler CA;Underhill DM;Goodridge HS;Lutz CM;Baloh RH
通讯作者：
Baloh RH
影响因子：
11.1
作者：
Henkel, Jenny S.;Beers, David R.;Wen, Shixiang;Rivera, Andreana L.;Toennis, Karen M.;Appel, Joan E.;Zhao, Weihua;Moore, Dan H.;Powell, Suzanne Z.;Appel, Stanley H.
通讯作者：
Appel, Stanley H.
影响因子：
5.5
作者：
Marchlik, Erica;Thakker, Paresh;Hall, J. Perry
通讯作者：
Hall, J. Perry
影响因子：
11.2
作者：
Henkel, JS;Engelhardt, JI;Appel, SH
通讯作者：
Appel, SH
影响因子：
2.6
作者：
Hayashi, Shigemi;Lewis, Paula;McMahon, Andrew P.
通讯作者：
McMahon, Andrew P.