title: NRAS mutation causes a human autoimmune lymphoproliferative syndrome.
abstract: 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(-) alphabeta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor 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 proapoptotic 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 farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders.
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: João B
authors.initials: JB
authors.lastname: Oliveira
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Cynthia P
authors.initials: CP
authors.lastname: Nix
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barb
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Janet
authors.initials: J
authors.lastname: Dale
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Straus
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007376:Interleukin-2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins