Liddle Syndrome 3

A number sign (#) is used with this entry because of evidence that Liddle syndrome-3 (LIDLS3) is caused by heterozygous mutation in the SCNN1A gene (600228), encoding the alpha subunit of the renal epithelial sodium channel (ENaC), on chromosome 12p13. One such family has been reported.

Description

Liddle syndrome, or pseudoaldosteronism, is an autosomal dominant form of salt-sensitive hypertension characterized by suppressed plasma renin and aldosterone, hypokalemia, and metabolic alkalosis (summary by Salih et al., 2017).

For a discussion of genetic heterogeneity of Liddle syndrome, see 177200.

Clinical Features

Salih et al. (2017) reported a family in which the male proband had resistant hypertension, hypokalemia, metabolic alkalosis, and suppressed levels of plasma renin and aldosterone, features consistent with pseudoaldosteronism, or Liddle syndrome. The epithelial sodium channel blocker triamterene normalized his blood pressure and serum potassium. A sister of the proband had mild hypertension that was sensitive to sodium chloride supplementation and also improved with triamterene. Their parents and 3 other sibs had hypertension without suppressed renin and aldosterone.

Molecular Genetics

In a male proband with Liddle syndrome, who was negative for mutation in 2 known Liddle syndrome-associated genes, Salih et al. (2017) performed exome sequencing and identified heterozygosity for a missense mutation in the SCNN1A gene (C479R; 600228.0009) that was also present in his affected sister, but not in other family members who had hypertension without suppression of plasma renin and aldosterone. Functional analysis demonstrated that the C479R change represents a gain-of-function mutation in the ENaC alpha subunit that causes increased intrinsic channel activity, which the authors noted is a mechanism different from previously reported Liddle syndrome-associated mutations in other ENaC subunits.