A New Presentation of the Chimeric CYP11B1/CYP11B2 Gene With Low Prevalence of Primary Aldosteronism and Atypical Gene Segregation Pattern

Carvajal, Cristián A.; Campino, Carmen; Martínez‐Aguayo, Alejandro; Tichauer, Juan E.; Bancalari, Rodrigo; Valdivia, Carolina; Trejo, Pamela; Aglony, Marlene; Baudrand, René; Lagos, Carlos F.; Mellado, Cecília; García, Hernán; Fardella, Carlos E.

doi:10.1161/hypertensionaha.111.180513

Cited by 24 publications

(15 citation statements)

References 45 publications

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“…Recently, we reported the unequal crossover break point in the CYP11B1/B2 gene [20]. The 50-bp crossover region contains segments of intron 3 of CYP11B1 (c.2937-40) and exon 4 of CYP11B2 (c.2937 + 10).…”

Section: Methodsmentioning

confidence: 99%

Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro

Vecchiola

Lagos

Fuentes

et al. 2013

Reprod Biol Endocrinol

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BackgroundFamilial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes.MethodsWe designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids.ResultsIn our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann–Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients.ConclusionsOur results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.

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Section: Methodsmentioning

confidence: 99%

Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro

Vecchiola

Lagos

Fuentes

et al. 2013

Reprod Biol Endocrinol

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“…In this family, the chimeric CYP11B1/CYP11B2 gene segregation differs from an autosomal disease, showing 100% of penetrance in generations II and III and 62.5% in generation IV. The authors suggested that this inheritance pattern was not due to random segregation but due to a preferential segregation of the chimeric CYP11B1/CYP11B2 gene in the offspring (Carvajal et al 2012). This may be explained by differential selection by viability of gametes, mitotic errors in germ cells, or differential survival of cells during…”

Section: Familial Hyperaldosteronism Type Imentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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“…Four forms of familial hyperaldosteronism (FH-1 to FH-IV) together with Primary Aldosteronism, Seizures, Neurological Abnormalities (PASNA) syndrome [2] [3] [4]. FH-I, also called glucocorticoid-remediable aldosteronism, accounts for only 0.5 to 1% of PA [5] .…”

Section: Introductionmentioning

confidence: 99%

“…A hallmark of familial hyperaldosteronism type I is the presence of a chimeric aldosterone synthase enzyme, which is formed by unequal crossing-over of the genes that encode 11β-hydroxylase (CYP11B1), and aldosterone synthase (CYP11B2) enzymes. These genes are 95% identical in nucleotide sequence [5][6][7][8]. The 11β-hydroxylase enzyme (CYP11B1 gene) is normally expressed in both: human adrenal fasciculate and glomerulose zones, catalyzes the biosynthesis of cortisol and aldosterone, respectively.…”

Section: Introductionmentioning

confidence: 99%

Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Vecchiola

Fuentes

Carvajal

et al. 2020

Preprint

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BackgroundFamilial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol did not affect.AimTo explore the direct action of testosterone on ASWT and ASCE enzymes.MethodsHEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities were evaluated incubating HEK-cells transfected with enzymes vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed.ResultsIn this system, testosterone inhibited ASWT (90% inhibition at five µM, IC50=1.690 µM) with higher efficacy and potency than ASCE (80% inhibition at five µM, IC50=3.176 µM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures.ConclusionsThe inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.

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A New Presentation of the Chimeric CYP11B1/CYP11B2 Gene With Low Prevalence of Primary Aldosteronism and Atypical Gene Segregation Pattern

Cited by 24 publications

References 45 publications

Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro

Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro

An update on novel mechanisms of primary aldosteronism

Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

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