Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome

Abstract

Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the beta subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the gamma subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of beta and gamma subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt-sensitive form of human hypertension.

Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits

“…Targeted disruption of the β or γ subunits in mice produces a similar phenotype [10,11]. Conversely, in Liddle's syndrome mutations in the β or γ subunits cause severe high blood pressure [12][13][14]. Na + channels containing the Liddle's mutation expressed in itro show at least twice the activity of normal channels and the turnover rate of mutant channels appears to be decreased [15,16].…”

Regulation of the Epithelial Na+ Channel by Cytosolic ATP

“…ENaC is composed of three partially homologous subunits, ␣, ␤, and ␥ (2, 3). The physiological importance of ENaC has been underscored by the recent identification of either loss of function mutations in the channel leading to pseudohypoaldosteronism (PHA1) (4 -6) or gain of function mutations causing pseudoaldosteronism (Liddle's syndrome), a hereditary form of arterial hypertension (7)(8)(9). Moreover, abnormally high ENaC activity has been associated with cystic fibrosis due to loss of the normal inhibitory effect of CFTR on ENaC (10 -13), and gene targeting of ␣ENaC in mice led to newborn death from pulmonary edema (14).…”

Monogenic forms of mineralocorticoid hypertension: insights into the pathogenesis of ‘essential’ hypertension?

“…The ␤-and ␥-subunits lie in close proximity on chromosome 16p and mutations in both the ␤-or ␥-subunits have been described in affected cases. 35,36 In each case these mutations cause deletions (45-75 aa) of the C-terminal portions of the subunit proteins producing a Na channel which is constitutively active. How this positive effect is mediated is uncertain, but it may result from induction of synthesis of new sodium channels.…”

“…Whilst it seems likely that these conditions will remain rare causes of hypertension, their detection may be difficult. Hypokalaemia is one obvious screening test, but it is now appreciated that up to 50% cases of genetically proven cases of GRA 64 and Liddle's syndrome 35,36 are normokalaemic and the absence of hypokalaemia does not exclude these conditions. A similar argument applies for the detection of primary aldosteronism.…”