Somatic mutations in SLC30A1 lead to aldosterone-producing adenomas and primary aldosteronism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236437 | GEO | 2023/07/03
REPOSITORIES: GEO
Similar Datasets
Project description:Analysis of aldosterone-producing adenoma (APA) samples from patients with primary hyperaldosteronism. These APAs have a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. Results provide insight into the different mechanisms each mutation may cause leading to elevated aldosterone production in APA. In this dataset, we include expression data from aldosterone-producing adenomas (APAs) with a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. These data are used to obtain differentially expressed genes between KCNJ5 mutant APAs and CACNA1D/ATP1A1 mutant APAs. A total of 13 samples were analyzed (8 KCNJ5 mutant APAs and 5 CACNA1D/ATP1A1 mutant APAs). 43 genes had a false discovery rate (FDR) <0.5% and were >2-fold different between KCNJ5 mutant APAs and 5 CACNA1D/ATP1A1 mutant APAs. The two sets of genotypes were separated on unsupervised hierarchical clustering of 1475 genes correlating >0.6 with CYP11B2.
2013-07-14 | E-GEOD-48303 | biostudies-arrayexpress
Project description:Analysis of aldosterone-producing adenoma (APA) samples from patients with primary hyperaldosteronism. These APAs have a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. Results provide insight into the different mechanisms each mutation may cause leading to elevated aldosterone production in APA. In this dataset, we include expression data from aldosterone-producing adenomas (APAs) with a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. These data are used to obtain differentially expressed genes between KCNJ5 mutant APAs and CACNA1D/ATP1A1 mutant APAs.
2013-07-14 | GSE48303 | GEO
Project description:Primary aldosteronism (PA), a common cause of severe hypertension, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) and 80 additional probands with unsolved early-onset PA. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset PA carried the CLCN2 variant found in probands. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. In this data set, we examined RNA expression in H295R cells transfected with empty vector, WT and p.Arg172Gln CLCN2. Expression of CLCN2 led to increased expression of CYP11B2 and its upstream regulator NR4A2.
2017-12-08 | GSE107030 | GEO
Project description:The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5, has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with KCNJ5 mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with KCNJ5 mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with KCNJ5 mutations.
2018-01-08 | GSE90867 | GEO
Project description:Primary aldosteronism (PA) is a common form of endocrine hypertension suspected in the presence of arterial hypertension (HT), hypokalemia and low plasma renin levels. While for a long time the genetic causes of PA have remained mysterious, recent findings have revealed an important role for an altered function of potassium channels in the pathogenesis of this disease. The basis for the unique sensitivity of adrenal zona glomerulosa (ZG) cells for plasma potassium concentration is a very high background potassium conductance, which is dependent on expression at high levels of two 2-pore domain (K2P) potassium channels, Task1 (KCNK3) and Task3 (KCNK9. Recent studies have shown that mice lacking Kcnk3 (Task1) or both Kcnk3 and Kcnk9 have PA. In Kcnk3 null mice, hyperaldosteronism is present in young animals of either sex, but is corrected in males after puberty. Strikingly, in these animals hyperaldosteronism associates with abnormal adrenal cortex functional zonation, since Cyp11b2, the rate-limiting enzyme for aldosterone production, is expressed in the inner region of the adrenal cortex and not in the glomerulosa. Additionally, this phenotype is under the control of sex hormones, as shown by the fact that castration of male Kcnk3 -/- animals prevents normal Cyp11b2 distribution, while testosterone injection in female Kcnk3 null mice restores expression of Cyp11b2 in ZG cells. We took advantage of the unique characteristics of the Kcnk3 null mouse model to search for genes that can modify their phenotype of PA and adrenocortical functional zonation. Using gene expression profiling in the adrenal glands of Kcnk3 null mice and exploiting the possibility of modulation of their phenotype by sexual hormones, we identified a cluster of genes closely associated with hyperaldosteronism in a sex- and hormone-dependent dynamic fashion. Among these genes, we focused our attention on Dkk3 (dickkopf3), encoding a peculiar member of the dickkopf family of Wnt signalling modulators because of its close association with aldosterone-producing cells in humans (11). Inactivation of Dkk3 in the Kcnk3 null background causes extension of the hyperaldosteronemic phenotype and increased expression of Cyp11b2 in the adrenal gland to the male sex, without affecting functional zonation. These data indicate that Dkk3 is a component of the genetic circuitry regulating expression of Cyp11b2 and suggest that it may be implicated in the pathogenesis of low-renin hyperaldosteronism in humans. One color -experiment with 2 strains of mice: C57BL/6 WT or Kcnk3 null (KO): male and female in basal conditions or following hormonal treatment (castration for males and testosterone injection for females), corresponding to 8 groups of animals. Total of 24 samples (n=3).
2012-08-20 | E-GEOD-37825 | biostudies-arrayexpress
Project description:Primary aldosteronism (PA) is a common form of endocrine hypertension suspected in the presence of arterial hypertension (HT), hypokalemia and low plasma renin levels. While for a long time the genetic causes of PA have remained mysterious, recent findings have revealed an important role for an altered function of potassium channels in the pathogenesis of this disease. The basis for the unique sensitivity of adrenal zona glomerulosa (ZG) cells for plasma potassium concentration is a very high background potassium conductance, which is dependent on expression at high levels of two 2-pore domain (K2P) potassium channels, Task1 (KCNK3) and Task3 (KCNK9. Recent studies have shown that mice lacking Kcnk3 (Task1) or both Kcnk3 and Kcnk9 have PA. In Kcnk3 null mice, hyperaldosteronism is present in young animals of either sex, but is corrected in males after puberty. Strikingly, in these animals hyperaldosteronism associates with abnormal adrenal cortex functional zonation, since Cyp11b2, the rate-limiting enzyme for aldosterone production, is expressed in the inner region of the adrenal cortex and not in the glomerulosa. Additionally, this phenotype is under the control of sex hormones, as shown by the fact that castration of male Kcnk3 -/- animals prevents normal Cyp11b2 distribution, while testosterone injection in female Kcnk3 null mice restores expression of Cyp11b2 in ZG cells. We took advantage of the unique characteristics of the Kcnk3 null mouse model to search for genes that can modify their phenotype of PA and adrenocortical functional zonation. Using gene expression profiling in the adrenal glands of Kcnk3 null mice and exploiting the possibility of modulation of their phenotype by sexual hormones, we identified a cluster of genes closely associated with hyperaldosteronism in a sex- and hormone-dependent dynamic fashion. Among these genes, we focused our attention on Dkk3 (dickkopf3), encoding a peculiar member of the dickkopf family of Wnt signalling modulators because of its close association with aldosterone-producing cells in humans (11). Inactivation of Dkk3 in the Kcnk3 null background causes extension of the hyperaldosteronemic phenotype and increased expression of Cyp11b2 in the adrenal gland to the male sex, without affecting functional zonation. These data indicate that Dkk3 is a component of the genetic circuitry regulating expression of Cyp11b2 and suggest that it may be implicated in the pathogenesis of low-renin hyperaldosteronism in humans.
2012-08-20 | GSE37825 | GEO
Project description:Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to major structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
2019-10-21 | GSE136801 | GEO
Project description:Primary and secondary hypertension are major risk factors for cardiovascular disease. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we identify an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by dysregulated zonation of the glomerulosa, increased aldosterone levels and aldosterone target gene expression, and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of PIAS1, an E3 SUMO-protein ligase implicated in the suppression of LXR. Notably, SIAH1 sequence variants which impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression, were identified in patients with PA. The involvement of Siah1–PIAS1 in adrenal gland organization and function points to a possible new therapeutic target for hyperaldosteronism.
2018-05-01 | GSE102963 | GEO
Project description:The source of aldosterone in 30 to 40 % of patients with primary hyperaldosteronism (PA) is unilateral aldosterone-producing adenoma (APA). The mechanisms causing elevated aldosterone production in APA are unknown. Herein, we examined expression of G-protein coupled receptors (GPCR) in APA and demonstrate that compared to normal adrenals there is a general elevation of certain GPCR in many APA and/or ectopic expression of GPCR in others. RNA samples from normal adrenals (n = 5), APAs (n = 10), and cortisol-producing adenomas (CPAs) (n=13) were used on 15 genomic expression arrays, each of which included 223 GPCR transcripts presented in at least one out of 15 of the independent microarrays. The array results were confirmed using real-time RT-PCR (qPCR). Four GPCR transcripts exhibited a statistically significant increase that was greater than 3-fold compared to normal adrenals, suggesting a general increase in expression compared to normal adrenal glands. Four GPCR transcripts exhibited a greater than 15-fold increase of expression in one or more of the APA samples compared to normal adrenals. qPCR analysis confirmed array data and found the receptors with the highest fold increase in APA expression to be luteinizing hormone receptor (LH-R), serotonin receptor 4 (HTR4), gonadotropin-releasing hormone receptor (GnRHR), glutamate receptor metabotropic 3 (GRM3), endothelin receptor type B-like protein (GPR37), and ACTH receptor (MC2R). There are also sporadic increased expressions of these genes in the CPAs. Together, these findings suggest a potential role of altered GPCR expression in many cases of PA and provide candidate GPCR for further study. Keywords: disease state analysis
2007-07-19 | GSE8514 | GEO
Project description:Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells . Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA. We conducted single-nuclei RNA sequencing (snRNA-seq) of APAs and non-functional adenomas (NFA) obtained from three and two patients, respectively.The snRNA-seq revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of NFA and APA. In addition, we extracted two cell differentiation pathways in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in one of these pathways, whereas those related to the regulation of actin cytoskeleton were upregulated in the other pathway. Furthermore, the total RNA reads in the nucleus were higher in highly differentiated clusters, indicating a marked activation of transcription per cell. The snRNA-seq provides novel differentiation pathways within APA tumors, which will further support our understanding of its pathophysiology including endocrine function and tumorigenesis.
2023-12-01 | GSE242404 | GEO