Niki Mourtzi1, Amalia Sertedaki2, Athina Markou3, George P Piaditis3, Nicholas Katsanis4, Joanne Traeger-Synodinos5, Constantine Tsigos6, Evangelia Charmandari1,7. 1. Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Aghia Sophia' Children's Hospital, 11527, Athens, Greece. 2. Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Aghia Sophia' Children's Hospital, 11527, Athens, Greece. aserted@med.uoa.gr. 3. Department of Endocrinology and Diabetes Center, G. Gennimatas General Hospital, 11527, Athens, Greece. 4. Department of Cell Biology and Pediatrics, School of Medicine and Rescindo Therapeutics, Northwestern University, Chicago, USA. 5. Laboratory of Medical Genetics, Choremeio Research Laboratory, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527, Athens, Greece. 6. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671, Athens, Greece. 7. Division of Endocrinology and Metabolism, Center of Clinical, Biomedical Research Foundation, Experimental Surgery and Translational Research, Academy of Athens, 11527, Athens, Greece.
Abstract
PURPOSE: Although ACTH is considered a secondary regulator of aldosterone production, patients with apparent essential hypertension have been treated with mineralocorticoid receptor antagonists (MRAs). In this study, we aimed to identify potentially damaging variants that might be implicated in the phenotype of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone hypersecretion. The patients' blood pressure was normalized though MRA administration. METHODS: Genetic screening was performed through whole-exome sequencing (WES), and variants in PA-associated or in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency < 0.01, predicted to alter protein structure and classified as likely pathogenic by in silico tools, were retained. RESULTS: Qualifying variants were identified in nine of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, and CACNA1D). A novel variant in the KCNK9 gene (p.V221M) is reported. Our analysis revealed two variants in two novel susceptibility genes for aldosterone hypersecretion, namely, KCNK16 (p.P255H) and CACNA2D3 (p.V557I). CONCLUSION: WES revealed potentially damaging germline variants in genes participating in aldosterone synthesis/regulating pathways in 9/21 patients of our cohort. The variants identified might play a role in aldosterone hypersecretion under conditions of stress. The potential pathogenicity of these variants should be examined in future functional studies.
PURPOSE: Although ACTH is considered a secondary regulator of aldosterone production, patients with apparent essential hypertension have been treated with mineralocorticoid receptor antagonists (MRAs). In this study, we aimed to identify potentially damaging variants that might be implicated in the phenotype of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone hypersecretion. The patients' blood pressure was normalized though MRA administration. METHODS: Genetic screening was performed through whole-exome sequencing (WES), and variants in PA-associated or in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency < 0.01, predicted to alter protein structure and classified as likely pathogenic by in silico tools, were retained. RESULTS: Qualifying variants were identified in nine of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, and CACNA1D). A novel variant in the KCNK9 gene (p.V221M) is reported. Our analysis revealed two variants in two novel susceptibility genes for aldosterone hypersecretion, namely, KCNK16 (p.P255H) and CACNA2D3 (p.V557I). CONCLUSION: WES revealed potentially damaging germline variants in genes participating in aldosterone synthesis/regulating pathways in 9/21 patients of our cohort. The variants identified might play a role in aldosterone hypersecretion under conditions of stress. The potential pathogenicity of these variants should be examined in future functional studies.
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