Liddle Syndrome 2

A number sign (#) is used with this entry because of evidence that Liddle syndrome-2 (LIDLS2) is caused by heterozygous mutation in the SCNN1G gene (600761), encoding the gamma subunit of the renal epithelial sodium channel (ENaC), on chromosome 16p12.

Description

Liddle syndrome is an autosomal dominant form of hypertension characterized by early onset of hypertension associated with hypokalemia, suppressed plasma renin activity, and suppressed secretion of the mineralocorticoid hormone aldosterone (summary by Hansson et al., 1995).

For a general phenotypic description and a discussion of genetic heterogeneity of Liddle syndrome, see 177200.

Clinical Features

Hansson et al. (1995) reported a Japanese family (K204) with clinically typical Liddle syndrome and showed that the disorder was caused by mutation in the gamma subunit of the epithelial sodium channel. The family was ascertained through a 17-year-old female who presented with lower limb numbness and was found to have hypokalemia and severe hypertension. Suppressed plasma renal activity and plasma aldosterone concentration was demonstrated, other steroids were normal, and there was no sign of virilization. Blood pressure and hypokalemia were not improved by the mineralocorticoid antagonists spironolactone or the glucocorticoid dexamethasone, but improved markedly in response to dietary salt restriction plus the epithelial sodium channel antagonist triamterene.

Hiltunen et al. (2002) reported a Finnish man who developed hypertension associated with low serum aldosterone, suppressed renin activity, and persistent hypokalemia at 25 years of age. His mother had been hypertensive since age 40 years and had a low-normal serum potassium with low plasma renin activity. The proband's blood pressure was initially resistant to treatment but responded to triamterene and later amiloride; similarly, his mother became normotensive when her treatment included amiloride.

Wang et al. (2007) studied a Japanese man who was first diagnosed with hypertension at 13 years of age. He had hypokalemic metabolic alkalosis and low plasma renin activity; serum aldosterone was in the low-normal range. Initial treatments for hypertension were ineffective, but after the diagnosis of Liddle syndrome was made, his blood pressure was controlled on triamterene and a low-sodium diet.

Inheritance

The findings in the pedigree with Liddle syndrome reported by Hansson et al. (1995) were consistent with autosomal dominant inheritance, although there was no male-to-male transmission.

Molecular Genetics

In affected members of a Japanese family (K204) segregating Liddle syndrome who did not have mutation in the SCNN1B gene (600760), Hansson et al. (1995) identified a truncating mutation in the C terminus of the gamma subunit of the renal epithelial sodium channel (W574X; 600761.0001).

Snyder et al. (1995) investigated the mechanism by which truncation of the C terminus of the beta and gamma subunits alter the function of the renal epithelial sodium channel. They identified a conserved motif in the C terminus of all 3 subunits of the sodium channel that, when mutated, reproduced the effect of Liddle truncations. Further, both truncation of the C terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C terminus of the beta subunit. Thus, by deleting a conserved motif, mutations in the Liddle syndrome increased the number of sodium channels in the apical membrane, which increases renal sodium absorption and creates a predisposition to hypertension.

In 3 affected members of a Chinese family with Liddle syndrome, Shi et al. (2010) identified a heterozygous nonsense mutation (Q567X; 600761.0002) in the SCNN1G gene.

In a Finnish man with hypertension, hypokalemia, low serum aldosterone, and suppressed renin activity, Hiltunen et al. (2002) screened the SCNN1B and SCNN1G genes and identified heterozygosity for a missense mutation in SCNN1G (N530S; 600761.0008). The mutation was also present in his affected mother, but was not found in his unaffected brother or maternal aunt. However, the N530S variant was detected in 1 of 291 healthy Finnish blood donors as well as in 1 of 175 control Finnish men, aged 50 to 69 years, who had low-normal blood pressure; neither individual was available for further evaluation. Functional analysis demonstrated a 2-fold increase in channel activity with the mutant compared to wildtype SCNN1G.

In a Japanese man with Liddle syndrome, Wang et al. (2007) screened the C terminus of the SCCN1B and SCNN1G genes and identified heterozygosity for a de novo 5-bp deletion in SCNN1G (600761.0009) that was not found in his unaffected parents, 50 randomly selected hypertensive patients, or 50 normotensive controls. The authors stated that this was the first reported sporadic patient with a mutation in the SCNN1G gene, and noted that Liddle syndrome should be considered in patients without a family history of hypertension.