Georgia Pitsava1,2, Fabio R Faucz2, Constantine A Stratakis2,3,4, Fady Hannah-Shmouni5. 1. Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 2. Section On Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 3. ELPEN Pharmaceuticals, Pikermi, Athens, Greece. 4. Human Genetics & Precision Medicine, IMBB, FORTH, Heraklion, Greece. 5. Section On Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. fshmouni@gmail.com.
Abstract
PURPOSE OF THE REVIEW: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. RECENT FINDINGS: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of β-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.
PURPOSE OF THE REVIEW: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. RECENT FINDINGS: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of β-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.
Authors: Paul Milliez; Xavier Girerd; Pierre-François Plouin; Jacques Blacher; Michel E Safar; Jean-Jacques Mourad Journal: J Am Coll Cardiol Date: 2005-04-19 Impact factor: 24.094
Authors: Stephen S Lim; Theo Vos; Abraham D Flaxman; Goodarz Danaei; Kenji Shibuya; Heather Adair-Rohani; Markus Amann; H Ross Anderson; Kathryn G Andrews; Martin Aryee; Charles Atkinson; Loraine J Bacchus; Adil N Bahalim; Kalpana Balakrishnan; John Balmes; Suzanne Barker-Collo; Amanda Baxter; Michelle L Bell; Jed D Blore; Fiona Blyth; Carissa Bonner; Guilherme Borges; Rupert Bourne; Michel Boussinesq; Michael Brauer; Peter Brooks; Nigel G Bruce; Bert Brunekreef; Claire Bryan-Hancock; Chiara Bucello; Rachelle Buchbinder; Fiona Bull; Richard T Burnett; Tim E Byers; Bianca Calabria; Jonathan Carapetis; Emily Carnahan; Zoe Chafe; Fiona Charlson; Honglei Chen; Jian Shen Chen; Andrew Tai-Ann Cheng; Jennifer Christine Child; Aaron Cohen; K Ellicott Colson; Benjamin C Cowie; Sarah Darby; Susan Darling; Adrian Davis; Louisa Degenhardt; Frank Dentener; Don C Des Jarlais; Karen Devries; Mukesh Dherani; Eric L Ding; E Ray Dorsey; Tim Driscoll; Karen Edmond; Suad Eltahir Ali; Rebecca E Engell; Patricia J Erwin; Saman Fahimi; Gail Falder; Farshad Farzadfar; Alize Ferrari; Mariel M Finucane; Seth Flaxman; Francis Gerry R Fowkes; Greg Freedman; Michael K Freeman; Emmanuela Gakidou; Santu Ghosh; Edward Giovannucci; Gerhard Gmel; Kathryn Graham; Rebecca Grainger; Bridget Grant; David Gunnell; Hialy R Gutierrez; Wayne Hall; Hans W Hoek; Anthony Hogan; H Dean Hosgood; Damian Hoy; Howard Hu; Bryan J Hubbell; Sally J Hutchings; Sydney E Ibeanusi; Gemma L Jacklyn; Rashmi Jasrasaria; Jost B Jonas; Haidong Kan; John A Kanis; Nicholas Kassebaum; Norito Kawakami; Young-Ho Khang; Shahab Khatibzadeh; Jon-Paul Khoo; Cindy Kok; Francine Laden; Ratilal Lalloo; Qing Lan; Tim Lathlean; Janet L Leasher; James Leigh; Yang Li; John Kent Lin; Steven E Lipshultz; Stephanie London; Rafael Lozano; Yuan Lu; Joelle Mak; Reza Malekzadeh; Leslie Mallinger; Wagner Marcenes; Lyn March; Robin Marks; Randall Martin; Paul McGale; John McGrath; Sumi Mehta; George A Mensah; Tony R Merriman; Renata Micha; Catherine Michaud; Vinod Mishra; Khayriyyah Mohd Hanafiah; Ali A Mokdad; Lidia Morawska; Dariush Mozaffarian; Tasha Murphy; Mohsen Naghavi; Bruce Neal; Paul K Nelson; Joan Miquel Nolla; Rosana Norman; Casey Olives; Saad B Omer; Jessica Orchard; Richard Osborne; Bart Ostro; Andrew Page; Kiran D Pandey; Charles D H Parry; Erin Passmore; Jayadeep Patra; Neil Pearce; Pamela M Pelizzari; Max Petzold; Michael R Phillips; Dan Pope; C Arden Pope; John Powles; Mayuree Rao; Homie Razavi; Eva A Rehfuess; Jürgen T Rehm; Beate Ritz; Frederick P Rivara; Thomas Roberts; Carolyn Robinson; Jose A Rodriguez-Portales; Isabelle Romieu; Robin Room; Lisa C Rosenfeld; Ananya Roy; Lesley Rushton; Joshua A Salomon; Uchechukwu Sampson; Lidia Sanchez-Riera; Ella Sanman; Amir Sapkota; Soraya Seedat; Peilin Shi; Kevin Shield; Rupak Shivakoti; Gitanjali M Singh; David A Sleet; Emma Smith; Kirk R Smith; Nicolas J C Stapelberg; Kyle Steenland; Heidi Stöckl; Lars Jacob Stovner; Kurt Straif; Lahn Straney; George D Thurston; Jimmy H Tran; Rita Van Dingenen; Aaron van Donkelaar; J Lennert Veerman; Lakshmi Vijayakumar; Robert Weintraub; Myrna M Weissman; Richard A White; Harvey Whiteford; Steven T Wiersma; James D Wilkinson; Hywel C Williams; Warwick Williams; Nicholas Wilson; Anthony D Woolf; Paul Yip; Jan M Zielinski; Alan D Lopez; Christopher J L Murray; Majid Ezzati; Mohammad A AlMazroa; Ziad A Memish Journal: Lancet Date: 2012-12-15 Impact factor: 79.321
Authors: Jenifer M Brown; Mohammed Siddiqui; David A Calhoun; Robert M Carey; Paul N Hopkins; Gordon H Williams; Anand Vaidya Journal: Ann Intern Med Date: 2020-05-26 Impact factor: 25.391
Authors: Ute I Scholl; Gerald Goh; Gabriel Stölting; Regina Campos de Oliveira; Murim Choi; John D Overton; Annabelle L Fonseca; Reju Korah; Lee F Starker; John W Kunstman; Manju L Prasad; Erum A Hartung; Nelly Mauras; Matthew R Benson; Tammy Brady; Jay R Shapiro; Erin Loring; Carol Nelson-Williams; Steven K Libutti; Shrikant Mane; Per Hellman; Gunnar Westin; Göran Åkerström; Peyman Björklund; Tobias Carling; Christoph Fahlke; Patricia Hidalgo; Richard P Lifton Journal: Nat Genet Date: 2013-08-04 Impact factor: 38.330