Endocrine Abstracts (2003) 6 S6

GENETIC DISORDERS OF MINERALOCORTICOIDS

PM Stewart


Division of Medical Sciences, University of Birmingham, Birmingham, UK.


A greater understanding of mineralocorticoid hormone action in recent years has facilitated the elucidation of the molecular basis of several 'salt-wasting' and 'salt-retaining' disorders.

In mineralocorticoid-responsive salt transporting epithelial cells of the distal nephron, colon and salivary gland, aldosterone or, depending upon the activity of 11beta hydroxysteroid dehydrogenase type 2 (11beta HSD2), cortisol, interacts with the mineralocorticoid receptor (MR) to induce target genes including serum and glucocorticoid regulated kinase (sgk1). Sgk1 phosphorylates a ubiquitin-protein ligase, Nedd4-2 that reduces its affinity for the subunits of the apical epithelial sodium channel (ENaC- comprising alpha, beta and gamma units) resulting in post-translational activation of existing sodium channels and increased epithelial sodium transport. 'Monogenic' forms of mineralocorticoid hypertension have been described that include inactivating mutations in the genes encoding 11beta HSD2 (Apparent Mineralocorticoid Excess), activating mutations in the beta and gamma ENaC sub units (Liddle's syndrome), a chimaeric 11beta hydroxylase /aldo synthase gene (glucocorticoid remediable hyperaldosteronism), and gain of function mutations in the MR.

Conversely mineralocorticoid deficiency is observed in pseudohypoaldosteronism (PHA). Several types have been described and the molecular basis recently identified. Corticosterone methyl oxidase (CMO) deficiency is an outdated term referring to mutations in aldo synthase and defective aldosterone biosynthesis. Pseduohypoaldosteronism type 1 encompasses two distinct variants, a recessively inherited disease caused by inactivating mutations in the ENaC subunits and mutations within the MR (autosomal dominant inheritance). All patients present with salt wasting crisis in neonatal life, though mutations in the MR are associated with a milder phenotype that usually improves with age. PHA type 2 or Gordon's syndrome is an autosomal dominant form of hyperkalaemia and hypertension with raised aldosterone concentrations due to impaired renal potassium excretion explained on the basis of mutations in a family of serine/threonine kinases (WNK1, WNK4).

Whilst these genetic defects are rare, they have provided candidate-susceptibility genes for lineage/association studies in patients with 'essential' hypertension.

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