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Status |
Public on Mar 21, 2008 |
Title |
Germline NRAS mutation causes a novel human autoimmune lymphoproliferative syndrome |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving tumor necrosis factor receptor (TNFR) superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling which markedly decreases the pro-apoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyl-transferase inhibitors (FTIs) should be examined in human autoimmune and lymphocyte homeostasis disorders. Keywords: NRAS
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Overall design |
Describes the discovery of a new gene underlying a novel type of autoimmune lymphoproliferative syndrome, and characterizes the mechanisms involved in the pathogenesis of the disease.
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Contributor(s) |
Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ |
Citation(s) |
17517660 |
Submission date |
Mar 22, 2007 |
Last update date |
Mar 25, 2019 |
Contact name |
Joao Bosco Oliveira |
E-mail(s) |
oliveirajb@lim56.fm.usp.br
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Phone |
+55-11-3061-7193
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Organization name |
University os São Paulo
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Department |
Dermatology
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Lab |
Molecular Immunology and Genetics Section, LIM-56
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Street address |
Av. Dr. Eneas de carvalho Aguiar, 500 IMT Bldg. II 3rd Floor
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City |
Sao Paulo |
State/province |
Sao Paulo |
ZIP/Postal code |
05430-000 |
Country |
Brazil |
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Platforms (1) |
GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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Samples (8)
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GSM177046 |
ALPS 1A PBMCs, 0h after IL-2 withdrawal |
GSM177047 |
ALPS 1A PBMCs, 24h after IL-2 withdrawal |
GSM177048 |
Normal control PBMCs, 0h after IL-2 withdrawal, biological replicate 1 |
GSM177049 |
Normal control PBMCs, 24h after IL-2 withdrawal, biological replicate 1 |
GSM177050 |
Normal control PBMCs, 0h after IL-2 withdrawal, biological replicate 2 |
GSM177051 |
Normal control PBMCs, 24h after IL-2 withdrawal, biological replicate 2 |
GSM177052 |
P58 PBMCs, 0h after IL-2 withdrawal |
GSM177053 |
P58 PBMCs, 24h after IL-2 withdrawal |
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Relations |
BioProject |
PRJNA100453 |
Supplementary file |
Size |
Download |
File type/resource |
GSE7345_RAW.tar |
34.2 Mb |
(http)(custom) |
TAR (of CEL) |
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