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Mendelian Forms of Human Hypertension and Mechanisms of Disease

Franz Volhard Clinic HELIOS Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany

REPRINT REQUESTS: Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany, Telephone: +49 30 9417 2202, Fax: +49 30 9417 2206, Email: luft{at}fvk-berlin.de

[See related article 271 – 272]

Mendelian forms of hypertension have ushered in a revolution in our knowledge of blood pressure and volume regulation. If we include information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the ß and subunits of ENaC cause Liddle’s syndrome. Loss-of-function mutations in all three subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all three subunits can be mutated, causing either hyper or hypotension. Three loci have been described for Gordon’s syndrome, pseudohypoaldosteronism type II. Two members of the WNK serine-threonine kinase family have recently been found to be responsible. Their function has been largely elucidated. Autosomal dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. Finally, at least 5 different genes have been described that when mutated can cause pheochromocytoma. Thus, the elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.

Key Words: Mendelian hypertension • Aldosteronism • Epithelial sodium channel • Liddle’s syndrome • Pseudohypoaldosteronism • Gordon’s syndrome • Brachydactyly • Pheochromocytoma

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