Genetic Variations in the KCNJ5 Gene in Primary Aldosteronism Patients from Xinjiang, China

P rimary hyperaldosteronism (PA) is now recognized as a common, treatable, and potentially curable form of hypertension. In fact it may account for ≥10% of cases of what would previously have been labeled as essential hypertension.1,2 The excessive aldosterone production usually derives from either an aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. The balance between these 2 pathologies varies; however, in most recently published series, bilateral adrenal hyperplasia is about twice as common as APA. 3,4 Although the majority of PA is sporadic, there are monogenic familial forms of the condition (familial hyperaldosteronism types I, II, and III [FH-I, FH-II, and FH-III]). The molecular basis for FHI, glucocorticoid-remediable aldosteronism, has been well understood for >2 decades and involves a recombination event that places the aldosterone synthase enzyme, CYP11B2, under the control of ACTH. 5,6 In contrast, the molecular genetics for FHIII has been resolved recently with the discovery that they are caused by germline mutations that cluster in the selectivity filter of a potassium channel, KCNJ5. 7-9 These mutations affect the Na + permeability of the channel, which is thought to lead to depolarization of zona glomerulosa cells in the adrenal cortex thereby activating aldosterone release.Before the discovery of selectivity filter mutations in KCNJ5, this potassium channel was not even recognized as being expressed in the human adrenal gland. However, it is now known to be important in sporadic as well as the much rarer syndromic forms of PA, 10 with ≤40% of APAs carrying somatic mutations in the same KCNJ5 gene. 7,11 The coding sequence for KCNJ5 has been resequenced in a large collection of adrenal lesions (both APAs and non-APAs) without identifying further somatic mutations outside of the selectivity filter itself. 12However, we hypothesized that rare variants, in the form of See Editorial Commentary, pp 668-669Abstract-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...

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“…21 However, this study identified a small increase in the frequency of an SNP in the noncoding 3′-UTR (rs2604204) whose functionality is unknown.…”

Section: Discussionmentioning

confidence: 81%

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

Murthy

Massimo

et al. 2014

Hypertension

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“…15 Interestingly, a recent study investigated the association of KCNJ5 single nucleotide polymorphisms and PA in Chinese patients; one of the polymorphisms, located in the 3′untrans-lated region, was associated with PA in male patients. 16 The functional effect of this polymorphism is unknown; however, an effect on mRNA stability or processing is not expected to cause hyperaldosteronism because variations in KCNJ5 expression (including silencing and overexpression) do not result in major changes in aldosterone secretion and, therefore, the significance of this association needs to be explored more in depth and confirmed in a different population.…”

Section: Hypertensionmentioning

confidence: 99%

KCNJ5 Mutations Are the Most Frequent Genetic Alteration in Primary Aldosteronism

2015

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“…The role of common KCNJ5 SNPs was also assessed in cohorts of Asian patients with PA and essential hypertension (Li et al 2013. Comparing 235 subjects with sporadic PA to 913 subjects with essential hypertension, Li and coworkers showed that in Chinese population, the minor allele of the KCNJ5 SNP rs2604204, located in the KCNJ5 3′-UTR, was more frequent in males with PA (43.4%) than that in males with essential hypertension (33.3%, P = 0.001) (Li et al 2013), suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in Chinese patients.…”

Section: Familial Hyperaldosteronism Type III and Germline Kcnj5 Mutamentioning

confidence: 99%

“…Comparing 235 subjects with sporadic PA to 913 subjects with essential hypertension, Li and coworkers showed that in Chinese population, the minor allele of the KCNJ5 SNP rs2604204, located in the KCNJ5 3′-UTR, was more frequent in males with PA (43.4%) than that in males with essential hypertension (33.3%, P = 0.001) (Li et al 2013), suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in Chinese patients. The same SNP was studied in 229 Chinese patients with newly diagnosed essential hypertension .…”

Section: Familial Hyperaldosteronism Type III and Germline Kcnj5 Mutamentioning

confidence: 99%

Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development.

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Genetic Variations in the KCNJ5 Gene in Primary Aldosteronism Patients from Xinjiang, China

Cited by 19 publications

References 30 publications

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

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

KCNJ5 Mutations Are the Most Frequent Genetic Alteration in Primary Aldosteronism

Somatic and inherited mutations in primary aldosteronism

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