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Series GSE7345 Query DataSets for GSE7345
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
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
 
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.
 
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
Phone +55-11-3061-7193
Organization name University os São Paulo
Department Dermatology
Lab Molecular Immunology and Genetics Section, LIM-56
Street address Av. Dr. Eneas de carvalho Aguiar, 500 IMT Bldg. II 3rd Floor
City Sao Paulo
State/province Sao Paulo
ZIP/Postal code 05430-000
Country Brazil
 
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (8)
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
Relations
BioProject PRJNA100453

Download family Format
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE7345_RAW.tar 34.2 Mb (http)(custom) TAR (of CEL)

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