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Analyses of a deactivation genetic variation in Ha-Ras proto oncogene identified in a patient wit premature aging and insulin resistance

ABSTRACT: Inherited genetic variants of insulin receptor induced cellular signaling have long been suspected to contribute to the development of type-2- diabetes mellitus. In this report we discuss a heterozygous mutation in the first coding exon of the proto-oncogene Ha-Ras (Ha-RasA11P) that we have identified in a patient with familial premature aging syndrome. The patient has atopic sklerodermic skin alterations, insulin resistance as well as disturbances in lipid metabolism. In vitro analyzes have shown that this mutation disrupted not only the signal transduction of the insulin receptor but also other receptor tyrosine kinases, such as IGF-1, EGF, PDGF. These results demonstrate that HA-Ras has a significant role in insulin sensitivity in humans. We used microarrays to determine differences in gene expression due to a deactivating Ha-Ras mutation reducing c-fos expression in a patient with lipodystrophy and a Werner-like syndrome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49566 | GEO | 2013/08/07

SECONDARY ACCESSION(S): PRJNA214310

REPOSITORIES: GEO

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Analyses of a deactivation genetic variation in Ha-Ras proto oncogene identified in a patient wit premature aging and insulin resistance

Project description:Inherited genetic variants of insulin receptor induced cellular signaling have long been suspected to contribute to the development of type-2- diabetes mellitus. In this report we discuss a heterozygous mutation in the first coding exon of the proto-oncogene Ha-Ras (Ha-RasA11P) that we have identified in a patient with familial premature aging syndrome. The patient has atopic sklerodermic skin alterations, insulin resistance as well as disturbances in lipid metabolism. In vitro analyzes have shown that this mutation disrupted not only the signal transduction of the insulin receptor but also other receptor tyrosine kinases, such as IGF-1, EGF, PDGF. These results demonstrate that HA-Ras has a significant role in insulin sensitivity in humans. We used microarrays to determine differences in gene expression due to a deactivating Ha-Ras mutation reducing c-fos expression in a patient with lipodystrophy and a Werner-like syndrome. Cultued fibroblasts of non diabetic controls and a patient with deactivating Ha-Ras mutation were analyzed at identical passage number and growth conditions without further additional treatment.

2013-08-07 | E-GEOD-49566 | biostudies-arrayexpress

Microarray analysis of mice with thyroid hormone receptor and RAS mutations.

Project description:Affymetrix GeneChip Mouse Gene 1.0 ST Array was used to study gene expression profiles in three groups of mice: with thyroid hormone receptor ThrbPV (ThrbPV/PV) mutation only, with RAS mutation (KrasG12D) only, and with both ThrbPV/PV and KrasG12D mutations. Three groups mice: with thyroid hormone receptor ThrbPV (ThrbPV/PV) mutation only, with RAS mutation (KrasG12D) only, and with both ThrbPV/PV and KrasG12D mutations. Each group has three biological replicates.

2015-09-22 | E-GEOD-61652 | biostudies-arrayexpress

Effects of KRAS (G13C) expression on transcriptome profiles assessed in HPCs differentiated from patient-derived iPS cells

Project description:How a single oncogenic RAS impacts non-transformed hematopoietic progenitor cells (HPCs) remains largely unknown. We therefore investigated how a monoallelic KRAS mutation (G13C) affected HPCs utilizing induced pluripotent stem cells (iPSCs) derived from two unrelated patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD).

2024-04-01 | GSE200600 | GEO

Homo sapiens

Project description:Analyses of a deactivation genetic variation in Ha-Ras proto oncogene identified in a patient wit premature aging and insulin resistance

| PRJNA214310 | ENA

Primary and ras keratinocytes plus TGFbeta1

Project description:We have compared the response to TGFbeta1 in normal and v-rasHa transduced primary mouse keratinocytes using NCI cDNA microarrays. This analysis reveals that Ha-ras alters global TGFbeta1 mediated gene expression in a gene specific manner. The expression pattern of TGFbeta1 immediate early response genes and down regulation of cell cycle control genes is not altered by Ha-ras but the induction of most extracellular matrix genes is blocked. Using Smad3 null keratinocytes, we find that the majority of TGFbeta1 responsive genes in primary keratinocytes are Smad3 dependent, but patterns of transcriptional responses suggest that the ability of Ha-ras to block TGFbeta1 mediated gene expression is not dependent on Smad3. However, the combination of oncogenic ras and loss of Smad3 prevents the TGFbeta1 dependent suppression of genes associated with cell cycle progression and apoptosis observed with either genotype alone. In addition several extracellular matrix genes are super-repressed by TGFbeta1 in the Ha-ras Smad3 null keratinocytes. These data provide a genomic framework for understanding how disruptions of TGFbeta signaling and oncogenic ras cooperate to promote premalignant progression of primary keratinocytes. Keywords: time series design

2008-12-02 | GSE3228 | GEO

Differential gene expression in Ki-RAS and Ha-RAS cell lines.

Project description:Comparison of gene expression in Ha-RAS transformed cells versus untransformed Caco-2. Comparison of gene expression in Ki-RAS transformed cells versus untransformed Caco-2.

2009-04-07 | GSE12203 | GEO

A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors

Project description:A missense change in RRAS2 (Gln72-to-Leu), analogous to the Gln61-to-Leu mutation of RAS oncoproteins, has been identified as a hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains unknown. Here, we show that R-RAS2(Q72L) is required for optimal tumorigenic activity of human cancer cells.

2022-03-04 | GSE179409 | GEO

Mus musculus

Project description:Establishing RAS mutation tropism

| PRJNA663179 | ENA

Expression profiling in WT vs CDKL5 mutated IPSCs

Project description:Mutations in the human CDKL5 gene have been associated with early onset seizure variant of Rett Syndrome. In order to investigate the potential involvement of CDKL5 in the regulation of gene expression, we compared expression profiles in WT vs CDKL5-mutated IPS clones from two patients (one male and one female) with different mutations using two-colour microarray experiments. For the female patient (CDKL5 mutation p.Gln347X) we compared one clone expressing the mutant CDKL5 allele to another clone from the same patient that expresses the wild-type allele. Maintenance of X chromosome inactivation and the resulting mono-allelic expression of CDKL5 were confirmed by androgen receptor assay and direct sequencing of CDKL5 mRNA. The clone derived from the male patient (CDKL5 mutation p.Thr288Ile) was compared to a clone derived from a normal newborn male. For each mutant/control pair four technical replicates were performed for a total of eight chip hybridizations.

2014-07-02 | E-MTAB-2223 | biostudies-arrayexpress

Transcription profiling of human peripheral blood mononuclear cells WITH a germline NRAS mutation vs controls reveals NRAScauses a novel human autoimmune lymphoproliferative syndrome (ALPS)

Project description: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. Experiment 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.

2008-04-04 | E-GEOD-7345 | biostudies-arrayexpress

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