ENAC Mutations

The ENAC channel in the distal tubule is responsible for sodium reabsorption. It is comprised of 2 alpha, 1 beta, and 1 gamma subunit with each encoded by a separate gene. Interestingly, mutations in ENAC can lead to two different and largely opposite phenotypes.

Gain-of-function mutations in the ENAC result in Liddle's syndrome, which is not surprisingly characterized by metabolic alkalosis, hypertension, hypokalemia. Despite behaving physiologically like patients with hyperaldosteronism, their aldosterone levels are suppressed. This condition can generally be treated with amiloride or triamterene (which inhibit the Enac channel some) and a Na restricted diet.

In contrast, loss-of-function mutations--usually in either the alpha or beta subunits--can result in type I pseudohypoaldosteronism. This is often (but not always) autosomal dominant in nature and causes severe salt-wasting in children which is unresponsive to mineralocorticoid treatment. It can be treated with a high Na diet.