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At least 19 recordsLinked to original sources
PubMed1992

The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity.

Glucocorticoid-suppressible hyperaldosteronism (GSH) is one variety of primary aldosteronism with hypertension and is inherited in an autosomal dominant mode. A recent report has indicated that GSH is caused by a gene duplication arising from unequal crossing over between the two genes, CYP11B1 and CYP11B2, encoding P-450(11 beta) and P-450C18, respectively (Lifton et al. Nature (1992) 355, 262-265). The nucleotide sequence analysis in the present study has demonstrated that unequal crossing over in the chimeric gene formed by the gene duplication occurs within the region from the 3'-portion of exon 4 through the 5'-portion of intron 4 in Australian GSH patients. Namely, the chimeric gene encodes a fused P-450 protein consisting of the amino-terminal side of P-450(11 beta) (encoded by exons 1-4 of CYP11B1) and the carboxyl-terminal side of P-450C18 (encoded by exons 5-9 of CYP11B2). When a cDNA corresponding to the chimeric gene is transfected into COS-7 cells, the fused P-450 protein expressed in the mitochondria exhibits steroid 18-hydroxylase or aldosterone synthase activity. These results provide the molecular genetic basis for the characteristic biochemical phenotype of GSH patients.

Animals↗
PubMed1992

Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients.

The gene for steroid 18-hydroxylase (P-450C18) has been recently assigned to encode corticosterone methyl oxidases Type I and Type II which were previously postulated to catalyze the final two steps in the biosynthesis of aldosterone in humans. Molecular genetic analysis of the P-450C18 gene is three patients from three different families affected with CMO II deficiency has indicated that a point mutation of CGG----TGG (181Arg----Trp) in exon 3 and one of GTG----GCG (386Val----Ala) in exon 7 occur exclusively in the gene of the patients. Analysis of PCR products by restriction enzymes (HapII and HphI) has indicated that the patients are homozygous and the unaffected parent is heterozygous for both mutations, in accordance with the established concept that CMO II deficiency is inherited in an autosomal recessive manner. These data clearly provide the molecular genetic basis for the characteristic biochemical phenotype of CMO II clinical variants.

Aldosterone↗
PubMed1992

18-hydroxylation in the Y-1 adrenal cell line: response to ACTH and to culture conditions.

The 18-hydroxylation of deoxycorticosterone in the Y-1 adrenal cell line was studied under various incubation and cell culture conditions and compared to 11 beta-hydroxylation. Repeated incubation of the substrate increased both 18- and 11 beta-hydroxylation in the Y-1 cells. Furthermore, both 18- and 11 beta-hydroxylation were increased with increased serum concentration and prolonged incubation time. While the increase in 11 beta-hydroxylation seemed to be independent of the type of serum, 18-hydroxylation was much more important in cells cultured in fetal or newborn calf serum supplemented medium than in those cultured in horse serum supplemented medium. As expected, ACTH treatment increased 11 beta-hydroxylation; however, it decreased 18-hydroxylation. The different regulation of these two hydroxylating pathways by ACTH, point to a heterogeneity of the cytochrome P-450(11) beta of the Y-1 cell line.

Adrenal Glands↗
PubMed1992

Molecular biology of rat steroid 11 beta-hydroxylase [P450(11 beta)] and aldosterone synthase [P450(11 beta, aldo)].

The molecular features of rat steroid 11 beta-hydroxylase [P450(11 beta)] and aldosterone synthase [P450(11 beta, aldo)] are discussed. P450(11 beta) is biosynthesized as a precursor form composed of 499 amino acids, having a 24-amino acid extension peptide. Two species of P450(11 beta, aldo) were identified; a precursor form of P450(11 beta, aldo)-1 is 510 amino acids long and has a 34-amino acid extension peptide, while that of P450(11 beta, aldo)-2 is 500 amino acids long and has a 24-amino acid extension peptide. The 286th amino acid of P450(11 beta, aldo)-1 is Glu, while that of P450(11 beta, aldo)-2 is Lys. The cDNA-expression studies showed that P450(11 beta, aldo)-1 had the aldosterone producing activity whereas P450(11 beta, aldo)-2 had no activity, suggesting that Glu286 of P450(11 beta, aldo) plays an important role in the catalysis. The amino acid sequence of a region in P450(11 beta) from Leu337 through Pro352 is highly conserved among the steroidogenic P450s. Functional expression studies on the cDNAs for two P450(11 beta)s showed that P450(11 beta) catalyzes the 11 beta-, 18- and 19-hydroxylations of 11-deoxycorticosterone, but not the aldosterone synthesis. P450(11 beta, aldo), on the other hand, catalyzes the conversion of 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone and aldosterone. The two P450(11 beta)s were also shown to catalyze the conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol and cortisone.

Amino Acid Sequence↗
PubMed1992

Functional expression of cDNAs for bovine 11 beta-hydroxylase-aldosterone synthases, P450(11 beta)-2 and -3 and their chimeras.

Two molecular species of bovine P450(11 beta), P450(11 beta)-2 and P450(11 beta)-3 have been identified, in which the amino acid differences were found at the 6th, 36th and 82nd positions from the NH2-termini of the mature proteins. They catalyzed the 11 beta-, 18- and 19-hydroxylation and aldosterone formation from 11-deoxycorticosterone, and the rate of production of 18-hydroxycorticosterone and aldosterone by P450(11 beta)-3 was greater than that by P450(11 beta)-2 [Morohashi et al., J. Biochem. 107 (1990) 635-640]. In this study, chimeric clones were constructed whose 6th, 36th and 82nd amino acid residues were exchanged with each other. Two original clones and six chimeric clones were expressed in COS-7 cells, and their steroidogenic activities studied. The ratio of aldosterone or 18-hydroxycorticosterone production to corticosterone production by one clone was compared with that of the other. The ratios for the four clones having Gly36 [P450(11 beta)-3 type] were 0.08-0.22, whereas those for the clones having Ser36 [P450(11 beta)-2 type] were 0.03-0.05, suggesting that the Gly36 structure is important for aldosterone production.

Animals↗
PubMed1992

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Alleles↗
PubMed1992

Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.

Corticosterone methyloxidase II (CMO-II) deficiency is an autosomal recessive disorder of aldosterone biosynthesis, characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone in serum. It is genetically linked to the CYP11B1 and CYP11B2 genes that, respectively, encode two cytochrome P450 isozymes, P450XIB1 and P450XIB2. Whereas P450XIB1 only catalyzes hydroxylation at position 11 beta of 11-deoxycorticosterone and 11-deoxycortisol, P450XIB2 catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18. To determine the molecular genetic basis of CMO-II deficiency, seven kindreds of Iranian-Jewish origin were studied in which members suffered from CMO-II deficiency. No mutations were found in the CYP11B1 genes, but two candidate mutations, R181W and V386A, were found in the CYP11B2 genes. When these mutations were individually introduced into CYP11B2 cDNA and expressed in cultured cells, R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11 beta-hydroxylase activity intact, whereas V386A caused a small but consistent reduction in the production of 18-hydroxycorticosterone. All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas eight asymptomatic subjects were homozygous for R181W alone and three were homozygous for V386A alone. These findings confirm that P450XIB2 is the major enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in in vitro assays is sufficient to synthesize normal amounts of aldosterone.

Base Sequence↗
PubMed1992

Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2.

Glucocorticoid-suppressible hyperaldosteronism (GSH) is an autosomal dominant form of familial hypertension. The biochemical abnormalities seen in this disorder may be remedied by administration of dexamethasone, implying that aldosterone synthesis is being abnormally regulated by corticotropin. The final three steps of aldosterone synthesis, 11 beta- and 18-hydroxylation and 18-oxidation, are mediated by a cytochrome P450 in the zona glomerulosa of the adrenal cortex termed CYP11B2. A related isozyme in the zona fasciculata, CYP11B1, is required for cortisol synthesis; this isozyme, which is normally expressed at much higher levels than CYP11B2, only has 11 beta-hydroxylase activity. These isozymes are encoded by genes on human chromosome 8q22. We have now studied four unrelated patients with GSH. We found that each patient has one chromosome that carries three CYP11B genes instead of two. This has presumably been generated by unequal meiotic crossing-over. The extra gene is a hybrid with 5' regulatory and coding regions corresponding to CYP11B1 and 3' coding regions from CYP11B2. The breakpoint is in intron 2 in two cases, intron 3 in one, and exon 4 in one. Cells transfected with hybrid cDNAs containing up to the first three exons of CYP11B1 synthesized aldosterone at levels near that of cells carrying normal CYP11B2, but cells transfected with hybrids containing the first five or more exons of CYP11B1 could not synthesize detectable amounts of aldosterone. These data demonstrate that GSH is caused by expression of a gene that is regulated like CYP11B1 but that encodes a protein able to synthesize aldosterone.

Blotting, Southern↗
PubMed1992

The inhibition of rat adrenal cytochrome P-45011 beta gene expression by androgens.

The synthetic androgen methylandrostenediol (MAD) and the naturally occurring one, testosterone, both bring about hypertensive cardiovascular disease when chronically administered to rats. The pathogenesis of this form of experimental hypertension is thought to result from inhibition of steroid 11 beta-hydroxylase activity. In contrast to the above androgens, 19-nortestosterone, androstenedione and dehydroepiandrosterone (DHEA) have been reported to be without effect in elevating blood pressure. To examine the mechanism(s) involved, we have in this study compared the effects of a number of androgens on adrenal cytochrome P- 45011 beta enzyme and mRNA steady state levels. These parameters were also correlated with the ability of adrenal mitochondria isolated from these groups to hydroxylate 11-deoxycorticosterone (DOC) to corticosterone and 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC). Rats treated for seven days with 10 mg per day of dihydrotestosterone, testosterone, 19-nortestosterone or MAD showed a profound decrease in cytochrome P-45011 beta mRNA levels (to less than 20% of controls). This was accompanied by similar changes in both the level and activity of the enzyme. Androstenedione and DHEA were less potent in effecting these changes. In addition, for MAD and testosterone we tested the dose dependence of these changes and found that increasing doses (0.1 mg to 10 mg per day) of either androgen caused progressive decreases in the parameters measured. To assess selectivity we also determined the steady state level of cytochrome P-450scc mRNA in rats treated with the various androgens. In contrast to what was found with cytochrome P-45011 beta, the mRNA transcript for cytochrome P-450scc was equal to or above control levels. We conclude that, in general, the extent of inhibition of cytochrome P-45011 beta enzyme and mRNA level by a given androgen correlates with its reported facility in producing hypertension in rats. Increased secretion of DOC continues to be a likely mechanism for the development of this hypertension but with some androgens extra-adrenal effects may be involved.

Adrenal Glands↗
PubMed1992

Effect of dietary sodium restriction on mRNA for aldosterone synthase cytochrome P-450 in rat adrenals.

Changes in the level of mRNA for aldosterone synthase cytochrome P-450 (cytochrome P-450aldo) in rats on dietary sodium restriction were studied by means of Northern and slot blot hybridization using an oligonucleotide probe that allowed differentiation of the message for this enzyme from that for cytochrome P-450(11)beta. These two enzymes have been shown to be highly homologous with each other, exhibiting 88% homology in their nucleotide sequences in the coding region. Upon sodium restriction for 2 weeks, cytochrome P-450aldo mRNA in rat adrenals increased 7-fold, whereas the cytochrome P-450(11) beta mRNA level in the same adrenals did not change significantly. The increase in cytochrome P-450aldo mRNA paralleled that in cytochrome P-450aldo protein, as analyzed by immunoblot technique. These results, together with our previous finding that angiotensin II induced cytochrome P-450aldo in rat adrenocortex [Shibata, H., Ogishima, T., Mitani, F., Suzuki, H., Murakami, M., Saruta, T., & Ishimura, Y. (1991) Endocrinology 128, 2534-2539], suggest that the production of cytochrome P-450aldo is regulated by angiotensin II at the pretranslational level, most likely at the transcriptional level.

Adrenal Glands↗
PubMed1992

The conversion of corticosterone to aldosterone is the site of the oxygen sensitivity of the bovine adrenal zona glomerulosa.

The dissociation of renin and aldosterone observed during hypoxia in vivo has been attributed to a direct inhibition of low oxygen on adrenal zona glomerulosa function. We have demonstrated that the adrenal zona glomerulosa production of aldosterone in vitro is directly proportional to a wide range of oxygen concentrations in the physiological range but that cortisol production from coincubated fasciculata cells is not oxygen sensitive. The present study examined the hypothesis that the sensitivity to O2 is limited to the aldosteronogenic late pathway. In order to localize the site of oxygen sensitivity, we measured endogenous pregnenolone production (early pathway) and the conversion of exogenous corticosterone to aldosterone (ALDO) (i.e. 18-hydroxylase activity) in adrenal cells treated with cyanoketone (3-beta-hydroxy-steroid dehydrogenase inhibitor). Acutely dispersed bovine adrenal glomerulosa cells (four experiments in pentuplicate) were incubated under low (5%) vs. normal (21%) O2 in the presence of cyanoketone (CK; 1 microM) and/or the following: corticosterone (500 ng/ml), angiotensin II (ANG II; 10 nM), or dibutyryl cAMP (1 mM). Conversion of exogenous corticosterone to ALDO in the presence of CK was inhibited by 41 +/- 1% under low O2. This was similar to the inhibitory effect of low O2 on ANG II-stimulated aldosterone production from endogenous precursors in the absence of CK (52 +/- 11% inhibition). Basal, ANG II-, and cAMP-stimulated endogenous pregnenolone production was not significantly reduced by low O2. In another experiment, glomerulosa cells were incubated under 5, 13, or 50% vs. 21% O2 in the presence of CK (1 microM) and different concentrations of corticosterone (10-1000 ng/ml). ALDO production was significantly inhibited by low O2 when corticosterone was greater than or equal to 500 ng/ml and ALDO was significantly augmented by high O2 when added corticosterone was 1000 ng/ml. We conclude that the conversion of corticosterone to ALDO (i.e. 18-hydroxylase) appears to be the primary site of oxygen sensitivity since 1) pregnenolone production was unaffected and 2) the magnitude of the inhibition of the conversion of corticosterone to ALDO by low O2 in the presence of CK was similar to the inhibition of ALDO production from endogenous precursors in the absence of CK. These studies demonstrate that oxygen sensitivity of the steroidogenic pathway is a unique, constitutive property of 18-hydroxylase, the enzyme which catalyzes the conversion of corticosterone to ALDO. We propose that the sensitivity of 18-hydroxylase to oxygen accounts for the dissociation of renin and aldosterone during hypoxia in vivo.

Aldosterone↗
PubMed1992

Zone-specific expression of aldosterone synthase cytochrome P-450 and cytochrome P-45011 beta in rat adrenal cortex: histochemical basis for the functional zonation.

Zonal distribution of aldosterone synthase cytochrome P-450 and cytochrome P-45011 beta in rat adrenocortex was investigated immunochemically using specific antibodies to these enzymes. Localization of aldosterone synthase cytochrome P-450 (cytochrome P-450aldo), a recently identified enzyme that converts deoxycorticosterone to aldosterone in rat adrenocortex was strictly confined to two or three outermost cell layers in the zona glomerulosa. In contrast, cytochrome P-45011 beta, which forms corticosterone, but not aldosterone, from deoxycorticosterone, was localized in the zona fasciculata-reticularis and not in the zona glomerulosa. Neither enzyme was detected in the medulla or the capsule. The functional zonation of adrenocortex with respect to aldosterone and corticosterone syntheses is, thus, ascribable to the localization of cytochromes P-450aldo and P-45011 beta in the respective zones. When rats were maintained under Na-depleted conditions for 10 days, the zona glomerulosa cells containing cytochrome P-450aldo proliferated to 10-15 layers, the thickness of which was 5-7-fold that in the nonstimulated rats. Proliferation of the cytochrome P-450aldo-positive cells into the zona fasciculata-reticularis was also observed along with arterial walls. Under these conditions, no significant change in the distribution of cytochrome P-45011 beta was noted. These results indicate that the angiotensin-II stimuli, which had been elicited by the low Na treatment, promoted proliferation of the glomerulosa cells, resulting in increased expression of cytochrome P-450aldo in rat adrenocortex.

Adrenal Cortex↗
PubMed1992

[Drug clearance as a decision aid for further invasive liver diagnosis--studies with hexobarbital as a model substrate].

The clearance of a drug predominantly metabolized in the liver may serve as an estimate of quantitative liver function. In 260 consecutive patients presenting with a history of liver disease and abnormal laboratory findings but without a current definite diagnosis we have measured the clearance of hexobarbital and investigated if low values in patients are able to support the decision for an invasive diagnostic procedure such as needle biopsy or laparoscopy. 250 mg of hexobarbital was given orally to the patients between 8 and 10 hrs p.m. 12 hrs later blood samples were taken. Hexobarbital was determined by gas chromatography with N-selective detection, and a single point clearance was calculated. We recommended liver biopsy or laparoscopy to all patients with a hexobarbital clearance below 2.7 ml/min/kg body weight (normal 2.66-5.34 ml/min/kg). 73 out of 260 patients showed a reduced hexobarbital clearance. In 44 patients blind liver biopsy (n = 14) or laparoscopy (n = 30) was performed, 29 patients refused an invasive diagnostic procedure. 17 out of 26 patients with the tentative diagnosis chronic hepatitis had already an incomplete or complete liver cirrhosis. In 11 out of 18 patients with the tentative diagnosis alcohol toxic liver injury we found a progressive portal fibrosis or complete liver cirrhosis. Reduced drug clearance reflecting quantitative liver function can be an indicator of advanced liver disease, thus adding substantially to the decision for further invasive diagnostic procedures.

Cytochrome P-450 CYP11B2↗
PubMed1992

Dietary potassium supplementation and sodium restriction stimulate aldosterone synthase but not 11 beta-hydroxylase P-450 messenger ribonucleic acid accumulation in rat adrenals and require angiotensin II production.

Increasing evidence indicates that the adrenal cortex of most mammalian species expresses distinct forms of cytochrome P-450(11 beta), a steroidogenic enzyme that catalyses the terminal steps in the biosynthesis of both glucocorticoids and mineralocorticoids. In the human, mouse, and rat, two genes have been isolated, designated CYP11B1 and CYP11B2. The product of CYP11B2 (aldosterone synthase) is required for the successive 11 beta-, 18-hydroxylations and 18-oxidation of deoxycorticosterone that lead to the production of aldosterone in the zona glomerulosa. In contrast, the product of CYP11B1 (11 beta-hydroxylase) mediates only the 11 beta-hydroxylation of deoxycorticosterone and 11-deoxycortisol. The recent identification of these two P-450(11 beta) isozymes mandates further analysis of their expression in different zones of the adrenal cortex, both under basal conditions and in response to conditions known to alter mineralocorticoid biosynthesis. To evaluate the expression of the two isozymes in different adrenocortical zones, we performed Northern blotting analyses with specific oligonucleotide probes that discriminated between the two forms of rat P-450(11 beta). The transcripts detected by the two probes were of similar size (2.7 kilobase), but differed in their zonal distribution: aldosterone synthase P-450 messenger RNA (mRNA) was detected only in zona glomerulosa, whereas 11 beta-hydroxylase P-450 was expressed in both zona fasciculata-reticularis and zona glomerulosa. Next, we analyzed the response of these two genes to various physiological and pharmacological interventions known to affect aldosterone biosynthesis. High potassium or low sodium diet given to rats for 1 week increased aldosterone synthase P-450 mRNA levels by approximately 5- and 6-fold, respectively. These increases, moreover, were significantly attenuated by treatment with captopril, an inhibitor of angiotensin-converting enzyme. In contrast, neither dietary manipulation significantly affected 11 beta-hydroxylase P-450 mRNA levels in any zone. Thus, stimulation of the terminal steps of aldosterone biosynthesis by variations in dietary intake of monovalent cations involves regulation of aldosterone synthase P-450 mRNA levels. Finally, captopril inhibited potassium induction of aldosterone synthase P-450 mRNA levels despite the presence of low plasma renin activity in the potassium-treated rats. This finding implicates intraadrenal angiotensin II formation in the effect of potassium on mineralocorticoid production.

Adrenal Glands↗
PubMed2026

Baxdrostat for the treatment of primary aldosteronism: current evidence.

Primary aldosteronism (PA) is a common form of secondary hypertension, estimated to affect up to 20% of individuals with resistant hypertension. High levels of aldosterone induce several genomic and nongenomic effects, which lead to comorbidities beyond high blood pressure (BP), including excess cardiovascular and renal risk. Adrenalectomy is the treatment of choice for unilateral PA, while mineralocorticoid receptor antagonists (MRAs) represent the standard medical treatment for PA. However, many individuals fail to achieve complete medical treatment responses. This may be partly due to treatment‑limiting adverse effects and to the inability of MRAs to target mineralocorticoid receptor–independent pathways. As a result, the nongenomic actions of aldosterone – which may remain elevated – are not fully blocked, and its detrimental effects may persist. Selective aldosterone synthase (CYP11B2) inhibition has recently emerged as an alternative strategy for treating uncontrolled and resistant hypertension. Through highly selective CYP11B2 inhibition, baxdrostat was reported to significantly lower systolic and diastolic BP, while reducing aldosterone levels, with relatively low rates of hyperkalemia or serious adverse events, in phase II and III trials (BrigHTN, FigHTN, BaxHTN). Similarly, in patients with confirmed PA, a phase II trial (SPARK-PA) reported significant BP reductions, with aldosterone-to-renin ratio improvements indicative of complete biochemical response. Several phase III trials are currently studying the potential of baxdrostat not only in PA (BaxPA), but also its impact on cardiovascular and renal outcomes (BaxDuo Arctic, BaxDuo Pacific, Prevent-HF). Baxdrostat might become an important therapeutic option for PA, particularly for patients who are not candidates for adrenalectomy, who decline it, or do not have complete response with MRAs. If long-term studies confirm benefits on cardiovascular and renal outcomes, baxdrostat could redefine the medical management of PA and potentially serve as an equally effective alternative to adrenalectomy in selected patients.

Humans↗
PubMed1992

Corticosterone methyl oxidase type II deficiency: a cause of failure to thrive and recurrent dehydration in early infancy.

Corticosterone methyl oxidase type II (CMO II) deficiency is an uncommon cause of salt-wasting in infancy. We describe a boy who presented with recurrent dehydration and severe failure to thrive in the first 3 months of life, associated with mild hyponatraemia (serum Na+ 127-132 mEq/l) and hyperkalaemia (serum K+ 5.3-5.9 mEq/l). The diagnosis was suggested by an elevated plasma renin activity (PRA): serum aldosterone ratio, and subsequently confirmed by an elevated serum 18-hydroxycorticosterone: aldosterone ratio. Treatment with 9 alpha-fluorohydroxycortisone normalized growth parameters and PRA levels. CMO II deficiency should be considered in infants with recurrent dehydration and failure to thrive, even when serum sodium and potassium levels are not strikingly abnormal.

18-Hydroxycorticosterone↗
PubMed2025

Somatic Mutations in MCOLN3 Are Associated With Aldosterone-Producing Adenomas.

BACKGROUND: Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions-the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating a pathological increase in aldosterone synthase expression and aldosterone production. Elucidating the exact mechanisms causing aldosterone excess in primary aldosteronism would further the development of targeted treatments and alleviate the global hypertension burden. METHODS: Next-generation sequencing analysis of formalin-fixed paraffin-embedded aldosterone-producing adenomas identified novel somatic variants in MCOLN3 (encoding the cation-permeable channel, TRPML3). Electrophysiological, fura-2 calcium measurements, gene expression, and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel MCOLN3 mutations. RESULTS: Three somatic MCOLN3 variants (p.Y391D, p.F415I, and p.N411_V412delinsI) were identified in aldosterone-producing adenomas from 4 male primary aldosteronism patients. Mutated MCOLN3 expressed in HAC15 cells resulted in a gain-of-function phenotype, which induced cell membrane depolarization and calcium influx and, in turn, triggered a significant increase in aldosterone synthase expression and aldosterone production. CONCLUSIONS: This is the first report of disease-causing MCOLN3 mutations in humans and the first to implicate mutated MCOLN3 as a driver of dysregulated aldosterone production in primary aldosteronism.

Humans↗