A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I.

UNLABELLED: Familial hyperaldosteronism type I (FH-I) is an autosomal dominant disorder caused by an unequal cross-over of the gene encoding steroid 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), giving rise to a chimeric CYP11B1/CYP11B2 gene that displays aldosterone synthase activity regulated by ACTH instead of angiotensin II. AIM: To report an unprecedented case of a de novo unequal crossover mutation between CYP11B1 and CYP11B2 genes causing FH-I. PATIENTS AND METHODS: The index case is a 45-yr-old Chilean male diagnosed with primary aldosteronism (PA). All family members were also studied: his biological parents, 1 brother, 6 sisters, 2 daughters, and 1 son. Plasma renin activity, serum aldosterone, and its ratio were measured in all patients. Genetic analyses were performed using long-extension PCR (XL-PCR), DNA sequencing and Southern blot methods. RESULTS: PA was diagnosed for the index case, 1 of his daughters, his son but not for his parents or siblings. XLPCR and Southern blotting demonstrated the presence of the chimeric CYP11B1/CYP11B2 gene solely in PA-affected subjects, suggesting a case of a de novo mutation. Sequence analysis showed the unequal cross-over CYP11B1/CYP11B2 at intron 2 (c.2600-273 CYP11B2). We also identified a polymorphism at the same intron (c.2600-145C>A CYP11B2) in the genome of the index case's father. CONCLUSION: We describe an unprecedented case of unequal cross-over mutation for the chimeric CYP11B1/CYP11B2 gene causing FH-I, which may be linked to a polymorphism in the index case's father germ line.

Primary aldosteronism can alter peripheral levels of transforming growth factor beta and tumor necrosis factor alpha.

UNLABELLED: Primary aldosteronism (PA) is the most common secondary cause of hypertension that has recently been implicated in alterations of the immune system and progression of cardiovascular disease. OBJECTIVE: To study the cytokines transforming growth factor beta1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10) in patients with PA and essential hypertensives (EH) and evaluate its association with the renin-angiotensin-aldosterone system. PATIENTS AND METHODS: We studied 26 PA and 52 EH patients as controls, adjusted by their blood pressure, body mass index, age, and gender. In both groups, PA and EH, we measured serum aldosterone (SA), plasma renin activity (PRA), and cytokines TGF- beta1, TNF-alpha, and IL-10. In addition, 17 PA patients were treated for 6 months with spironolactone, a mineralocorticoid receptor (MR) antagonist. RESULTS: PA patients had lower levels of TGF-beta1 (17.6+/-4.1 vs 34.5+/-20.5 pg/ml, p<0.001) and TNF-alpha (17.0+/-4.4 vs 35.6+/-21.7 pg/ml, p<0.001) and similar IL-10 levels (99.7+/-18.7 vs 89.4+/-49.5 pg/ml, p: ns), as compared with EH controls. TGF-beta1 and TNF-alpha levels showed a remarkable correlation with SA/PRA ratio in the total group (PA+EH). The treatment of PA patients with spironolactone increased the TGF-beta1 levels (18.3+/-5.9 to 28.4+/-6.3 pg/ml, p<0.001), while TNF-alpha, and IL-10 remained unchanged. CONCLUSION: Our results showed that PA patients have lower TGF-beta1 and TNF-alpha cytokine serum levels than EH. TGF-beta1 levels were restored with spironolactone, showing a MR-dependent regulation. In this way, the chronic aldosterone excess modifies the TGF-beta1 levels, which could produce an imbalance in the immune system homeostasis that may promote an early proinflammatory cardiovascular phenotype.