Liddle Syndrome
Liddle's syndrome is an autosomal dominant disease. It is recognised by early and severe hypertension. With irregualtion in blood pressure, testing for Liddle's syndrome involves the measurement of plasma renin, plasma aldersterone and blood electrolyte levels. These would be found to be abnormally low in a patient with Liddle's syndrome.
Genetic Basis
Liddle mutation is in the C terminus of the beta and gamma subunits, which play a key role in trafficking the ENaC protein. The mutated region, called the PY motif (Pro-Pro-X-Tyr) is a binding site for Nedd4-2. The Nedd4-2 binds ENaC PY motif via its WW domain [1]. This normally leads to ubiquitylation and endocytosis reducing the number of ENaC in the plasma membrane [2]. AA motif within the C terminus is required for binding of Nedd4. Once Nedd4 is bound it regulates attachment of ubiquitin and triggers endocytosis of ENaC. Mutation therefore increases ENaC expression, increasing salt, blood volume and ultimately blood pressure.
Treatment
Amiloride, a diuretic, is used in the treatment of Liddle's syndrome. It works by inhibition of ENaC and so inhibition of sodium reabsorption and so water without depleting potassium levels.
References
- ↑ Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D: WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. Embo J 1996 , 15(10):2371-2380
- ↑ Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D: Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. Embo J 1997 , 16(21):6325-6336