Gene Summary

Gene:KCNJ5; potassium channel, inwardly rectifying subfamily J, member 5
Aliases: CIR, GIRK4, KATP1, LQT13, KIR3.4
Summary:Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. It may associate with two other G-protein-activated potassium channels to form a heteromultimeric pore-forming complex. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:G protein-activated inward rectifier potassium channel 4
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Phenotype
  • Chromosome 11
  • Cytochrome P-450 CYP11B2
  • Mutation
  • Base Sequence
  • Adrenal Cortex
  • Young Adult
  • Plasma Membrane Calcium-Transporting ATPases
  • Patch-Clamp Techniques
  • Potassium
  • Calcium Channels, L-Type
  • Veins
  • Sequence Alignment
  • Hypertension
  • Zona Glomerulosa
  • Pheochromocytoma
  • Hyperaldosteronism
  • Neoplasm Proteins
  • Hyperplasia
  • Cancer Gene Expression Regulation
  • Risk Factors
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Adrenal Glands
  • Transfection
  • Sodium
  • Pheochromocytoma and Paraganglioma
  • Calcium
  • Aldosterone
  • Molecular Sequence Data
  • Cell Line
  • Messenger RNA
  • Adrenocortical Cancer
  • Genetic Predisposition
  • Adrenocortical Adenoma
  • Cohort Studies
  • Sodium-Potassium-Exchanging ATPase
  • DNA Mutational Analysis
  • Adenoma
  • Cardiovascular Diseases
  • Point Mutation
  • Adrenocortical Cancer
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KCNJ5 (cancer-related)

Funder JW
Genetics of primary aldosteronism.
Front Horm Res. 2014; 43:70-8 [PubMed] Related Publications
Primary aldosteronism (PA) accounts for ∼10% of hypertension, which is commonly caused by an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Germline mutations producing PA are considered rare and termed familial hyperaldosteronism (FH) [1, 2, 3]. Since early 2011, a series of somatic mutations confined to the adrenal cortex has been reported, accounting for about half of APA. These mutations are in genes encoding components of the Kir 3.4 (GIRK4) potassium channel (KCNJ5), sodium/potassium and calcium ATPases (ATP1A1 and ATP2B3) and a voltage-dependent C-type calcium channel (CACNA1D). FH-1 (glucocorticoid-remediable hyperaldosteronism) results from a chimeric gene (5'-end of CYP11B1 fused to 3'-end of CYP11B2) and accounts for ∼1% of PA. FH-3 is very rare, is caused by bilateral expression of mutant KCNJ5 and usually results in florid hyperaldosteronism requiring early bilateral adrenalectomy. FH-2 is the most common form of hereditary PA (2 first-degree relatives with either an APA or bilateral adrenal hyperplasia) and currently thought to represent ∼6% of PA; the true prevalence may be considerably higher. The mutation(s) causing FH-2 are unknown but appear dominant, as is the case for FH-1 and FH-3. No studies have been done on possible recessive forms of PA.

Fernandes-Rosa FL, Williams TA, Riester A, et al.
Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma.
Hypertension. 2014; 64(2):354-61 [PubMed] Related Publications
Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options.

Dekkers T, ter Meer M, Lenders JW, et al.
Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit?
J Clin Endocrinol Metab. 2014; 99(7):E1341-51 [PubMed] Related Publications
CONTEXT: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia.
OBJECTIVE: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs.
DESIGN AND METHODS: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi.
RESULTS: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes.
CONCLUSIONS: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.

Beldjord K, Chevret S, Asnafi V, et al.
Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.
Blood. 2014; 123(24):3739-49 [PubMed] Related Publications
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

Fischer E, Beuschlein F
Novel genes in primary aldosteronism.
Curr Opin Endocrinol Diabetes Obes. 2014; 21(3):154-8 [PubMed] Related Publications
PURPOSE OF REVIEW: Novel high-throughput genetic techniques have increased the pace of discoveries in the field of primary aldosteronism. Mutations in the potassium channel gene KCNJ5 are a cause of familial and sporadic forms of primary aldosteronism with around 30-40% of aldosterone-producing adenomas being affected by somatic mutations.
RECENT FINDINGS: Exome sequencing of tumors without KCNJ5 mutations revealed genetic alterations in the ATPases ATP1A1 and ATP2B3, with a combined prevalence of 5-7%. Mutations in the gene encoding a subunit of the Ca channel Cav1.3 (CACNA1D) were described with a prevalence of 5-8%. In addition, a new syndrome consisting of primary aldosteronism, seizures, and neuromuscular disease with germline CACNA1D mutations could be identified. All these genetic variants enhance Ca-mediated signalling and steroidogenesis in affected glomerulosa cells and provide the molecular basis for autonomous aldosterone secretion. Furthermore, the pattern of genetic alterations allows for subgrouping of patient cohorts with potentially distinct clinical features including sex and age distribution as well as endocrine and cardiovascular endpoints.
SUMMARY: Altogether in around 50% of aldosterone-producing adenomas, a somatic point mutation can be identified as the underlying genetic cause. These findings will provide the framework for potential identification of new biomarkers and therapeutic targets of this most common form of secondary hypertension.

Tauber P, Penton D, Stindl J, et al.
Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas.
Endocrinology. 2014; 155(4):1353-62 [PubMed] Related Publications
Somatic mutations of the potassium channel KCNJ5 are found in 40% of aldosterone producing adenomas (APAs). APA-related mutations of KCNJ5 lead to a pathological Na(+) permeability and a rise in cytosolic Ca(2+), the latter presumably by depolarizing the membrane and activating voltage-gated Ca(2+) channels. The aim of this study was to further investigate the effects of mutated KCNJ5 channels on intracellular Na(+) and Ca(2+) homeostasis in human adrenocortical NCI-H295R cells. Expression of mutant KCNJ5 led to a 2-fold increase in intracellular Na(+) and, in parallel, to a substantial rise in intracellular Ca(2+). The increase in Ca(2+) appeared to be caused by activation of voltage-gated Ca(2+) channels and by an impairment of Ca(2+) extrusion by Na(+)/Ca(2+) exchangers. The mutated KCNJ5 exhibited a pharmacological profile that differed from the one of wild-type channels. Mutated KCNJ5 was less Ba(2+) and tertiapin-Q sensitive but was inhibited by blockers of Na(+) and Ca(2+)-transporting proteins, such as verapamil and amiloride. The clinical use of these drugs might influence aldosterone levels in APA patients with KCNJ5 mutations. This might implicate diagnostic testing of APAs and could offer new therapeutic strategies.

Murthy M, Xu S, Massimo G, et al.
Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism.
Hypertension. 2014; 63(4):783-9 [PubMed] Related Publications
Primary aldosteronism (autonomous aldosterone production with suppressed renin) plays an important pathophysiological role in what has been previously labeled as essential hypertension. Besides the recently described germline mutations in the KCNJ5 potassium channel associated with familial primary aldosteronism, somatic mutations in the same channel have been identified within aldosterone-producing adenomas. In this study, we have resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 white subjects with primary aldosteronism to look for rare variants that might be important for the pathophysiology of sporadic primary aldosteronism. We have identified 3 heterozygous missense mutations (R52H, E246K, and G247R) in the cohort and found that 12 (5% of the cohort) were carriers for the rare nonsynonymous single nucleotide polymorphism rs7102584 causing E282Q substitution of KCNJ5. By expressing the channels in Xenopus oocytes and human adrenal H295R cells, we have shown that the R52H, E246K, and E282Q substitutions are functional, but the G247R mutation is indistinguishable from wild type. Although the functional substitutions are remote from the selectivity filter, they affect the inward-rectification, the ability of the KCNJ5 channels to conduct Na(+) currents and ATII-induced aldosterone release from the H295R cell line. Together these data suggest that germline variation in the KCNJ5 gene has a role to play in the common sporadic form as well as the much rarer syndromic forms of primary aldosteronism.

Felizola SJ, Nakamura Y, Ono Y, et al.
PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues.
J Mol Endocrinol. 2014; 52(2):159-67 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Purkinje cell protein 4 (PCP4) is a calmodulin (CaM)-binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA), but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol-producing adenomas (n=15), and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than WT (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic, and neoplastic human adrenocortical cells.

Dillon ST, Bhasin MK, Feng X, et al.
Quantitative proteomic analysis in HCV-induced HCC reveals sets of proteins with potential significance for racial disparity.
J Transl Med. 2013; 11:239 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: The incidence and mortality of hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) is higher in African Americans (AA) than other racial/ethnic groups in the U.S., but the reasons for this disparity are unknown. There is an urgent need for the discovery of novel molecular signatures for HCV disease progression to understand the underlying biological basis for this cancer rate disparity to improve the clinical outcome.
METHODS: We performed differential proteomics with isobaric labeling tags for relative and absolute quantitation (iTRAQ) and MS/MS analysis to identify proteins differentially expressed in cirrhotic (CIR) and HCC as compared to normal tissues of Caucasian American (CA) patients. The raw data were analyzed using the ProteinPilot v3.0. Searches were performed against all known sequences populating the Swiss-Prot, Refseq, and TrEMBL databases. Quality control analyses were accomplished using pairwise correlation plots, boxplots, principal component analysis, and unsupervised hierarchical clustering. Supervised analysis was carried out to identify differentially expressed proteins. Candidates were validated in independent cohorts of CA and AA tissues by qRT-PCR or Western blotting.
RESULTS: A total of 238 unique proteins were identified. Of those, around 15% were differentially expressed between normal, CIR & HCC groups. Target validation demonstrates racially distinct alteration in the expression of certain proteins. For example, the mRNA expression levels of transferrin (TF) were 2 and18-fold higher in CIR and HCC in AA as compared to CA. Similarly; the expression of Apolipoprotein A1 (APOA1) was 7-fold higher in HCC of AA. This increase was mirrored in the protein expression levels. Interestingly, the level of hepatocyte nuclear factor4a (HNF4a) protein was down regulated in AA, whereas repression of transcription is seen more in CA compared to AA. These data suggest that racial disparities in HCC could be a consequence of differential dysregulation of HNF4a transcriptional activity.
CONCLUSION: This study identifies novel molecular signatures in HCV-induced HCC using iTRAQ-based tissue proteomics. The proteins identified will further enhance a molecular explanation to the biochemical mechanism(s) that may play a role in HCC racial disparities.

Williams TA, Monticone S, Schack VR, et al.
Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas.
Hypertension. 2014; 63(1):188-95 [PubMed] Related Publications
Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein-activated inward rectifier K(+) channel 4, GIRK4, account for ≈40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3, encoding Na(+)/K(+)-ATPase 1 and Ca(2+)-ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na(+)/K(+)-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na(+)/K(+)-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP11B2 gene expression and its transcriptional regulator NR4A2. Structural modeling of the Na(+)/K(+)-ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na(+) activation of phosphorylation and K(+) inhibition of phosphorylation that indicate decreased Na(+) and K(+) binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na(+)/K(+)-ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.

Palma P, Cuadros M, Conde-Muíño R, et al.
Microarray profiling of mononuclear peripheral blood cells identifies novel candidate genes related to chemoradiation response in rectal cancer.
PLoS One. 2013; 8(9):e74034 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Preoperative chemoradiation significantly improves oncological outcome in locally advanced rectal cancer. However there is no effective method of predicting tumor response to chemoradiation in these patients. Peripheral blood mononuclear cells have emerged recently as pathology markers of cancer and other diseases, making possible their use as therapy predictors. Furthermore, the importance of the immune response in radiosensivity of solid organs led us to hypothesized that microarray gene expression profiling of peripheral blood mononuclear cells could identify patients with response to chemoradiation in rectal cancer. Thirty five 35 patients with locally advanced rectal cancer were recruited initially to perform the study. Peripheral blood samples were obtained before neaodjuvant treatment. RNA was extracted and purified to obtain cDNA and cRNA for hybridization of microarrays included in Human WG CodeLink bioarrays. Quantitative real time PCR was used to validate microarray experiment data. Results were correlated with pathological response, according to Mandard´s criteria and final UICC Stage (patients with tumor regression grade 1-2 and downstaging being defined as responders and patients with grade 3-5 and no downstaging as non-responders). Twenty seven out of 35 patients were finally included in the study. We performed a multiple t-test using Significance Analysis of Microarrays, to find those genes differing significantly in expression, between responders (n = 11) and non-responders (n = 16) to CRT. The differently expressed genes were: BC 035656.1, CIR, PRDM2, CAPG, FALZ, HLA-DPB2, NUPL2, and ZFP36. The measurement of FALZ (p = 0.029) gene expression level determined by qRT-PCR, showed statistically significant differences between the two groups. Gene expression profiling reveals novel genes in peripheral blood samples of mononuclear cells that could predict responders and non-responders to chemoradiation in patients with locally advanced rectal cancer. Moreover, our investigation added further evidence to the importance of mononuclear cells' mediated response in the neoadjuvant treatment of rectal cancer.

Monticone S, Hattangady NG, Penton D, et al.
a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III.
J Clin Endocrinol Metab. 2013; 98(11):E1861-5 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
CONTEXT: Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes the inward rectifier K(+) channel 4 (G protein-activated inward rectifier K(+) channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the pathogenesis of sporadic aldosterone-producing adenomas.
OBJECTIVE: The objective of the study was to characterize the effects of a newly described KCNJ5 mutation in vitro.
PATIENTS AND METHODS: The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5 was PCR amplified from adrenal tissue and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 expression.
RESULTS: KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-to-cysteine substitution resulted in pathological Na(+) permeability, cell membrane depolarization, and disturbed intracellular Ca(2+) homeostasis, effects similar, albeit smaller, to the ones demonstrated for other KCNJ5 mutations. Gene expression studies revealed an increased expression of CYP11B2 and its transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5(Y152C) compared to the wild-type channel. The effect was clearly Ca(2+)-dependent, because it was abolished by the calcium channel blocker nifedipine.
CONCLUSIONS: Herein we describe a new germline mutation in KCNJ5 responsible for FH-III.

Yuan D, Ye S, Pan Y, et al.
Long-term cadmium exposure leads to the enhancement of lymphocyte proliferation via down-regulating p16 by DNA hypermethylation.
Mutat Res. 2013; 757(2):125-31 [PubMed] Related Publications
Cadmium (Cd) is a well-established carcinogen, however, the underlying mechanism, especially the role of epigenetics in it, is still poorly understood. Our previous work has disclosed that when rats were exposed to 0.5mg CdCl2 (kgd) for 8 and 12 weeks, the growth of peripheral white blood cells (WBC) was obviously stimulated but no over-proliferation of granulocyte-monocyte (GM) progenitor cells was observed in the bone marrow, suggesting that the over-proliferation of lymphocyte was promoted by Cd exposure. Is DNA-methylation involved in this Cd-stimulated cell proliferation? The present study found that when human B lymphoblast HMy2.CIR cells were exposed to Cd with a dose lower than 0.1μM for 3 months, both cell proliferation and mRNA expressions of DNA methyltransferases of DNMT1 and DNMT3b were increased, while the mRNA of tumor suppressor gene p16 was remarkably decreased. Furthermore, the level of genomic DNA methylation was increased and the CpG island in p16 promoter was hypermethylated in the Cd-exposed cells. A DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), diminished Cd-stimulated cell proliferation associated with p16 overexpression. Our results suggested that the chronic exposure of low dose Cd could induce hypermethylation of p16 promoter and hence suppress p16 expression and then promote cell proliferation, which might contribute to Cd-induced carcinogenesis.

Scholl UI, Goh G, Stölting G, et al.
Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
Nat Genet. 2013; 45(9):1050-4 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

Velarde-Miranda C, Gomez-Sanchez EP, Gomez-Sanchez CE
Regulation of aldosterone biosynthesis by the Kir3.4 (KCNJ5) potassium channel.
Clin Exp Pharmacol Physiol. 2013; 40(12):895-901 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The G-protein-activated inwardly rectifying potassium channel Kir3.4 is expressed in the zona glomerulosa cell membrane and transports potassium out of the cell.  Angiotensin II stimulation of aldosterone secretion is mediated, in part, by suppression of the transcription of KCNJ5, the gene coding for Kir3.4, and blocking channel activity. This results in membrane depolarization, mobilization of intracellular calcium, activation of the calcium-calmodulin pathway and increasing gene transcription of steroidogenic enzymes required for aldosterone secretion.  In 40-60% of aldosterone-producing adenomas there is a somatic mutation in the region of the KCNJ5 gene that codes for the selectivity filter that decreases potassium selectivity, allowing sodium to leak into the cells, thus depolarizing the membrane and initiating events that result in increased aldosterone synthesis.  The mechanism by which mutated KCNJ5 induces cell proliferation and adenoma formation remains unclear.

Arnesen T, Glomnes N, Strømsøy S, et al.
Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway.
Langenbecks Arch Surg. 2013; 398(6):869-74 [PubMed] Related Publications
BACKGROUND: Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway.
METHODS: Twenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status.
RESULTS: Ten out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type.
CONCLUSIONS: KCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).

Eckert C, Henze G, Seeger K, et al.
Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group.
J Clin Oncol. 2013; 31(21):2736-42 [PubMed] Related Publications
PURPOSE: In children with intermediate risk of relapse of acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. We hypothesized that the prognosis of patients with unsatisfactory reduction of minimal residual disease (MRD) can be improved by allogeneic hematopoietic stem-cell transplantation (HSCT).
PATIENTS AND METHODS: In the Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002, patients with an MRD level of ≥ 10(-3) (n = 99) at the end of induction therapy were allocated to HSCT, whereas those with an MRD level less than 10(-3) (n = 109) continued to receive chemotherapy. MRD was quantified by real-time polymerase chain reaction for clone-specific T-cell receptor/immunoglobulin gene rearrangements.
RESULTS: The probability of event-free survival for patients with MRD ≥ 10(-3) was 64% ± 5% in ALL-REZ BFM 2002 compared with 18% ± 7% in the predecessor study ALL-REZ BFM P95/96 (P < .001). This was mainly achieved by reducing the cumulative incidence of subsequent relapse (CIR) at 8 years from 59% ± 9% to 27% ± 5% (P < .001). The favorable prognosis of patients with MRD less than 10(-3) could be confirmed in those with a late combined or isolated bone marrow B-cell precursor (BCP) -ALL relapse (CIR, 20% ± 5%), whereas patients with an early combined BCP-ALL relapse had an unfavorable outcome (CIR, 63% ± 13%; P < .001).
CONCLUSION: Allogeneic HSCT markedly improved the prognosis of patients with intermediate risk of relapse of ALL and unsatisfactory MRD response. As a result, outcomes in this group approximated those of patients with favorable MRD response. Patients with early combined relapse require treatment intensification even in case of favorable MRD response, demonstrating the prognostic impact of time to relapse.

Zarate AM, Brezzo MM, Secchi DG, et al.
Malignancy risk models for oral lesions.
Med Oral Patol Oral Cir Bucal. 2013; 18(5):e759-65 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
OBJECTIVES: The aim of this work was to assess risk habits, clinical and cellular phenotypes and TP53 DNA changes in oral mucosa samples from patients with Oral Potentially Malignant Disorders (OPMD), in order to create models that enable genotypic and phenotypic patterns to be obtained that determine the risk of lesions becoming malignant.
STUDY DESIGN: Clinical phenotypes, family history of cancer and risk habits were collected in clinical histories. TP53 gene mutation and morphometric-morphological features were studied, and multivariate models were applied. Three groups were estabished: a) oral cancer (OC) group (n=10), b) oral potentially malignant disorders group (n=10), and c) control group (n=8).
RESULTS: An average of 50% of patients with malignancy were found to have smoking and drinking habits. A high percentage of TP53 mutations were observed in OC (30%) and OPMD (average 20%) lesions (p=0.000). The majority of these mutations were GC TA transversion mutations (60%). However, patients with OC presented mutations in all the exons and introns studied. Highest diagnostic accuracy (p=0.0001) was observed when incorporating alcohol and tobacco habits variables with TP3 mutations.
CONCLUSIONS: Our results prove to be statistically reliable, with parameter estimates that are nearly unbiased even for small sample sizes. Models 2 and 3 were the most accurate for assessing the risk of an OPMD becoming cancerous. However, in a public health context, model 3 is the most recommended because the characteristics considered are easier and less costly to evaluate.

Yoon JH, Kim HJ, Shin SH, et al.
BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML.
Eur J Haematol. 2013; 91(2):112-21 [PubMed] Related Publications
No consecutive analysis of BAALC and WT1 expressions associated with core-binding factor AML (CBF-AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real-time quantitative polymerase chain reaction (RQ-PCR) at diagnosis, after induction chemotherapy, at pre-HSCT, and at post-HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post-remission treatment. BAALC and WT1 RQ-PCR decrement ratio (DR) was also calculated at post-induction chemotherapy, at pre-HSCT, and at post-HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post-HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post-HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2-log at post-HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post-HSCT BAALC and WT1 expressions in patients with CBF-AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT.

Hoyos M, Nomdedeu JF, Esteve J, et al.
Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease.
Eur J Haematol. 2013; 91(3):209-18 [PubMed] Related Publications
PURPOSE: Most patients with acute myeloid leukemia (AML) and genetic rearrangements involving the core binding factor (CBF) have favorable prognosis. In contrast, a minority of them still have a high risk of leukemia recurrence. This study investigated the adverse features of CBF AML that could justify investigational therapeutic approaches.
PATIENTS AND METHODS: One hundred and fifty patients (median age 42 yr, range 16-69) with CBF AML (RUNX1-RUNX1T1 n = 74; CBFB-MYH11 n = 76) were prospectively enrolled into two consecutive CETLAM protocols at 19 Spanish institutions. Main clinic and biologic parameters were analyzed in the whole series. In non-selected cases with available DNA samples, the impact of molecular characterization and minimal residual disease (MRD) was also studied.
RESULTS: Overall, complete remission (CR) rate was 89% (94% in ≤50 yr old and 72% in >50 yr, P = 0.002). At 5 yr, cumulative incidence of relapse (CIR) was 26 ± 1%, disease-free survival (DFS) 62 ± 6%, and overall survival (OS) 66 ± 4%. In multivariate analyses, leukocyte count above 20 × 10(9) /L, BAALC over-expression, and high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy (CT) led to increased relapse rate. Regarding OS, age >50 yr, leukocyte count above 20 × 10(9) /L, and increased MN1 expression were adverse features.
CONCLUSION: Age, leukocyte counts, BAALC, and MN1 gene expressions as well as high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy are useful tools to predict the outcome and should be considered for risk-adapted therapy.

Zennaro MC, Rickard AJ, Boulkroun S
Genetics of mineralocorticoid excess: an update for clinicians.
Eur J Endocrinol. 2013; 169(1):R15-25 [PubMed] Related Publications
Aldosterone plays a major role in the regulation of sodium and potassium homeostasis and blood pressure. More recently, aldosterone has emerged as a key hormone mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism (PA), the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. PA represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid-remediable aldosteronism, one of the three Mendelian forms of PA, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone-producing adenoma (APA) and in familial hyperaldosteronism type 3. Moreover, recent findings have shown somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of APAs. This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population and the genetics of familial and sporadic PA. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production are also discussed. Finally, we outline the cardiovascular, renal, and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation.

Nomdedéu JF, Hoyos M, Carricondo M, et al.
Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML.
Leukemia. 2013; 27(11):2157-64 [PubMed] Related Publications
We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44 ± 3 vs 36 ± 3%, P=0.023; leukemia-free survival (LFS): 47 ± 3 vs 36 ± 4%, P=0.038; and cumulative incidence of relapse (CIR): 37 ± 3 vs 47 ± 4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59 ± 4%, LFS:59 ± 4% and CIR: 26 ± 4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48 ± 5%, LFS:41 ± 4% and CIR: 45 ± 4%); and Group 2 (WT1 >170.5 copies, 71 patients, OS: 23 ± 6%, LFS: 19 ± 7% and CIR: 68 ± 8%) (P<0.001). Post-intensification samples distinguished three groups: patients with WT1 >100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT1 <10 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30 ± 7%, 59 ± 4%, 72 ± 5%), LFS (24 ± 7%, 46 ± 4%, 65 ± 5%) and relapse probability (CIR 72 ± 7%, 45 ± 4%, 25 ± 5%), all P<0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.

Wang J, Dai Y, Huang Y, et al.
All-trans retinoic acid restores gap junctional intercellular communication between oral cancer cells with upregulation of Cx32 and Cx43 expressions in vitro.
Med Oral Patol Oral Cir Bucal. 2013; 18(4):e569-77 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
OBJECTIVE: All-trans retinoic acid (ATRA) has been demonstrated to inhibit tumor growth by restoration of gap junctional intercellular communication (GJIC) via upregulation of connexin (Cx) expression in some solid tumors. However, the relationship between ATRA and GJIC remains unclear in oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the effect of ATRA on the GJIC function of OSCC.
STUDY DESIGN: We measured the effects of ATRA on the viability and cell cycle distribution of SCC9 and Tca8113 OSCC cells. The GJIC function was observed using the scrape-loading dye transfer technique, and the mRNA and protein levels of Cx32 and Cx43 were detected by qRT-PCR, Western blot, and immunofluorescence assays.
RESULTS: ATRA inhibited the growth of OSCC cells in a dose- and time-dependent manner (P <0.05) and caused cell cycle arrest. ATRA-treated cells showed a 2.69-fold and 2.06-fold enhancement of GJIC in SCC9 and Tca8113 cells, respectively (P <0.05). Moreover, ATRA induced upregulation of Cx32 and Cx43 at both the mRNA and protein levels in OSCC cells.
CONCLUSION: Our results indicated that restoration of GJIC via enhanced Cx32 and Cx43 expression might serve as a novel mechanism for the anti-tumor effect of ATRA in OSCC.

Losso GM, Moraes Rda S, Gentili AC, Messias-Reason IT
Microsatellite instability--MSI markers (BAT26, BAT25, D2S123, D5S346, D17S250) in rectal cancer.
Arq Bras Cir Dig. 2012 Oct-Dec; 25(4):240-4 [PubMed] Related Publications
BACKGROUND: Colorectal cancer has an important genetic component. Microsatellites are considered phenotypic markers of prognosis, therapeutic response and identify patients with mutations in DNA repair genes.
AIM: To evaluate the molecular profile of tumors underwent to transanal endoscopic microsurgery-TEM in surgical treatment of rectal cancer.
METHOD: Thirty eight surgical specimens were evaluated according to pathological staging and the region of the tumor were dissected and submitted to DNA extraction. The colorectal tumors were tested for microsatellite instability-MSI using a panel of five markers (BAT25, BAT26, D2S123, D5S346, and D17S2720) technique of Polymerase Chain Reaction (PCR).
RESULT: From total 63% were male and 47% female, with mean age of 58.4 years. In relation to tumor type adenomas were 58%, 24% low-grade adenomas and 76% high grade; 42% were carcinomas. The depth of resection 80% included the rectal perirenal fat and 20% the muscularis propria. The most frequent microsatellite amplification was BAT26 (100%) and lowest D17S2720 (85.4%). Sixteen patients (42%) were MSI, ten were carcinomas, two low grade adenomas and four high grade. Twenty-two cases (68%) showed microsatellite stable-MSS. The allelic loss of microsatellite markers was statistically significant in cases of carcinoma in relation to adenomas. The most frequent microsatellite amplification was BAT26 (100%) and lower D17S2720 (85.4%), 16 patients (42%) had microsatellite instability-MSI thereof ten were carcinomas, two low grade adenomas, four high-grade adenomas and 22 cases (58%) were microsatellite stable-MSS.
CONCLUSION: Microsatellite instability (MSI-H) was significantly associated with rectal carcinomas, confirming its use as a prognostic marker in colorectal carcinogenesis.

Kohaar I, Porter-Gill P, Lenz P, et al.
Genetic variant as a selection marker for anti-prostate stem cell antigen immunotherapy of bladder cancer.
J Natl Cancer Inst. 2013; 105(1):69-73 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10(-11); n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10(-5); n = 173) and T1 (P = 2.64×10(-5); n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer.

Eckert C, von Stackelberg A, Seeger K, et al.
Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.
Eur J Cancer. 2013; 49(6):1346-55 [PubMed] Related Publications
PURPOSE: This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).
METHODS: Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.
RESULTS: Molecular good responders (MRD < 10(-3), n=46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ≥ 10(-3), n=34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p<0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p<0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.
CONCLUSION: In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.

Seccia TM, Mantero F, Letizia C, et al.
Somatic mutations in the KCNJ5 gene raise the lateralization index: implications for the diagnosis of primary aldosteronism by adrenal vein sampling.
J Clin Endocrinol Metab. 2012; 97(12):E2307-13 [PubMed] Related Publications
CONTEXT: Somatic mutations in the selectivity filter of KCNJ5 K(+) channel were found to be associated with higher plasma aldosterone concentrations in the patients with an aldosterone-producing adenoma (APA).
OBJECTIVE: We investigated whether plasma aldosterone levels and the lateralization index are higher from the side with the APA with the mutation, as compared with those without the mutation.
DESIGN: From 170 consecutive APA patients with comprehensive clinical and KCNJ5 data and a conclusive diagnosis, we recruited 91 patients with adrenal vein sampling and follow-up data. We measured CYP11B1 and CYP11B2 mRNA in APA tissue and plasma aldosterone (PAC) and plasma cortisol concentrations (PCC) in adrenal vein blood. To determine whether KCNJ5 mutations affected aldosterone output from the APA, we calculated the lateralization index (defined as the ratio of PAC to PCC at the APA side over the PAC to PCC ratio at the contralateral side). We also calculated two indexes of the aldosterone production from the APA side and the contralateral suppression index.
RESULTS: The mRNA content of CYP11B2, but not of CYP11B1, and, accordingly, the lateralization index was higher (29.9 ± 7.4 vs. 10.3 ± 3.6, P < 0.02) in the APA with the mutation than in the APA without the mutation.
CONCLUSIONS: APA patients with the somatic KCNJ5 mutations showed a higher production of aldosterone than those without such mutations, which translates in a higher lateralization index. Thus, they are more likely to be identified at adrenal vein sampling and therefore to receive adrenalectomy.

Yamada M, Nakajima Y, Taguchi R, et al.
KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas.
Endocr J. 2012; 59(8):735-41 [PubMed] Related Publications
Adrenal aldosterone-producing adenomas (APA) are rarely associated with the clear co-secretion of cortisol. Somatic mutations of the potassium channel KCNJ5 gene, with the hotspots G151R and L168R, have been recently identified in patients with APA. However, whether APAs that secrete cortisol have these mutations remains unclear. We examined three patients with APAs showing clear autonomous secretion of cortisol who possessed a 1 mg dexamethasone suppression test (DST) with a failure of the serum cortisol level to drop below 3.0 μg/dL, a morning plasma ACTH level of less than 10 pg/mL, and suppressed accumulation in the intact adrenal on (131)I- adosterol scintigraphy, or postoperative adrenal insufficiency. Laparoscopic adrenectomy revealed all tumors to be golden yellow, and histological examination confirmed them to be adrenocortical adenomas. All these patients required replacement therapy with hydrocortisone after surgery. Sequencing demonstrated that 2 of three cases showed a mutation of the KCNJ5 gene, one with c.451G>A, p.G151R and one with c.503T>G, p.L168R. Furthermore, the mRNA levels of steroidogenic enzymes including CYP11B1, CYP11B2, HSD3B2, CYP17A1, CYP11A1 and KCNJ5 in the 3 cases did not differ from those in 8 pure APAs not showing any of the above conditions for autonomous cortisol secretion. In addition, all 8 pure APAs harbored mutations of the KCNJ5 gene. These findings suggested that at least some aldosterone- and cortisol-co-secreting adrenal tumors have mutations of the KCNJ5 gene, suggesting the origin to be APA, and pure APAs may show a high incidence of KCNJ5 mutations.

Åkerström T, Crona J, Delgado Verdugo A, et al.
Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.
PLoS One. 2012; 7(7):e41926 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
MATERIALS AND METHODS: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.
RESULTS: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).
DISCUSSION: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Murthy M, Azizan EA, Brown MJ, O'Shaughnessy KM
Characterization of a novel somatic KCNJ5 mutation delI157 in an aldosterone-producing adenoma.
J Hypertens. 2012; 30(9):1827-33 [PubMed] Related Publications
OBJECTIVE: Adrenal aldosterone-producing adenomas (APAs) are an increasingly recognized cause of primary aldosteronism, and somatic mutations within the KCNJ5 gene encoding an inwardly rectifying K(+) channel (also called GIRK4 or Kir3.4) have been identified by several groups including our own. We identified the previously noted G151R and L168R mutations in the region of a selectivity filter of the channel as well as a previously unreported 3-base deletion, delI157. Here, we report the functional properties of KCNJ5 channels carrying this novel delI157 mutation.
METHODS: The delI157 mutation was introduced into wild-type KCNJ5 sequences to allow its expression in both H295R cells and Xenopus oocytes to study its expression and electrophysiology, respectively.
RESULTS: In the adrenal cell line H295R, the delI157 mutant expresses and traffics normally to the cell surface. However, the current-voltage behavior of the mutant in oocytes is distinct from wild-type channels and mimics closely other selectivity filter mutations. In particular, its ability to support substantial current when extracellular K(+) is replaced by Na(+). We also report for the first time that the mutants have reduced sensitivity to the KCNJ5 inhibitor tertiapin-Q that binds to the external vestibule of the channel pore.
CONCLUSION: This novel KCNJ5 mutation behaves like the three selectivity filter mutations previously reported in APAs depolarizing the cell and showing reduced cation selectivity. The reduced sensitivity to tertiapin-Q suggests that the abnormal Na(+) permeability of these selectivity mutations does indeed reflect structural changes around the mouth of the ion channel.

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