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Background Liddle’s syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) β or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle’s syndrome or Liddle’s-like syndrome, no previous report has indicated that Liddle’s-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria. Case presentation A 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle’s syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the β or γ subunits of the ENaC gene was not identified. Conclusion We reported for the first time a case of Liddle’s-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria.

Advances in genetic mapping and sequencing techniques have led to substantial progress in the study of rare monogenic (Mendelian) forms of abnormal blood pressure. Many disease-defining pathways for hypertension have been identified in the past two decades. Perturbations in renal salt handling appear to be a common mechanism underlying these rare syndromes of hypertension. Excess activation at various points in the mineralocorticoid signaling pathway and malfunctioning of the autonomic (specifically sympathetic) nervous system have both been implicated in inducing hypertension, while complementary studies examining low blood pressure phenotypes have identified novel pathways exclusively linked to renal salt wasting in either the thick ascending limb or the distal nephron. The genetic defects and the physiological and cellular pathways affected in these various disorders are reviewed here. Importantly, studies have suggested that genetic variation affecting these same genes and pathways may play an important role in explaining the variation of blood pressure levels in the general population. The investigation of rare syndromes of human blood pressure variation has important implications for improving the diagnosis and treatment of hypertension.

Liddle's syndrome has been known as a disorder associated with abnormal sodium reabsorption in the distal tubule and transmitted as a rare autosomal dominant trait. It is caused by mutations in the SCNN1B or SCNN1C gene, which truncate the cytoplasmic carboxyl terminus of the beta and gamma subunit of the epithelial sodium channel (ENaC). Genetic analysis of ENaC in a Chinese family with Liddle's syndrome revealed P616H of SCNN1B coaggregated with the phenotype, while this variant was not detected in 100 unrelated subjects. No mutation at gamma ENaC could be detected in all members of the family. P616H is located in the conserved proline-rich PY motif of the betaENaC. The PY motif can interact with the WW domain in Nedd4 and affect the activity of ENaC. Structural bioinformatics analysis confirmed that the functional interaction between Nedd4 and ENaC reduces in Liddle-ENaC (P616H) when compared with wild-type ENaC. In summary, P616H may be an underlying mechanism for the signs and symptoms of this family.

Regulation of the epithelial sodium channel (ENaC) is important for the long-term control of arterial blood pressure as evidenced by gain of function mutations of ENaC causing Liddle's syndrome, a rare form of hereditary arterial hypertension. In Xenopus laevis oocytes expressing ENaC a spontaneous decline of ENaC currents over time, so-called rundown, is commonly observed. Mechanisms involved in rundown may be physiologically relevant and may be related to feedback regulation of ENaC by intra- or extracellular Na+. We tested the effect of extracellular Na+ removal on ENaC rundown. Spontaneous rundown of ENaC was largely prevented by extracellular Na+ removal and was partially prevented by primaquine suggesting that it is due to endocytic channel retrieval. Liddle's syndrome mutation caused a reduced rate of rundown, and in oocytes expressing the mutated channel extracellular Na+ removal not only prevented rundown but even increased the ENaC currents (runup). Acute exposure to high extracellular Na+ drastically reduced whole-cell currents and surface expression of wild-type ENaC, while these effects were much smaller in ENaC with Liddle's syndrome mutation consistent with a stabilization of the mutated channel in the plasma membrane. Interestingly, the apparent intracellular Na+ concentration [Na+](i-app) was high (60 mM) in ENaC-expressing oocytes but rundown was not associated with a further increase in [Na+](i-app). We conclude that the inhibitory effect of extracellular Na+ removal on rundown is due to an inhibition of endocytic ENaC retrieval.

The 14-year follow-up of a female patient with Liddle's syndrome (LS), a rare disease characterized by hypertension, hypokalemic alkalosis, and negligible aldosterone secretion due to renin suppression, is described. The disease was diagnosed at the age of 10 months (youngest identification). The patient was repeatedly investigated during follow-up for plasma renin activity (PRA), plasma aldosterone concentration (PA), serum sodium and potassium (K) concentration, blood pressure (BP), somatic anthropometry, and mental development. Noteworthy results included: persistent low circulating K, PRA, and PA and high BP, coinciding with unauthorized withdrawal of the triamterene therapy. These findings are in keeping with the hypothesis that LS results from a pathogenetic disorder which is not correctable with age. The triamterene therapy was effective in correcting the endocrine and metabolic disorders as well as arterial hypertension, but did not prevent a deficit in mental and physical development. However, the information derived from this study allows further clarification of the clinical picture of the disease.

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.

The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of human hypertension thought to result from a deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme normally converts cortisol to inactive cortisone and is postulated to thus confer specificity for aldosterone upon the mineralocorticoid receptor. We have analysed the gene encoding the kidney isozyme of 11 beta HSD and found mutations on both alleles in nine of 11 AME patients (eight of nine kindreds). These mutations markedly affect enzymatic activity. They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension.

Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.

Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel. We demonstrate complete linkage of the gene encoding the beta subunit of the epithelial sodium channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.

A 10-month boy was found to have pseudoaldosteronism (Ps. Ald.) characterized by hypertension (178/116), alkalosis (HCO3–35 mEq/1, pH-7.50), hypokalemia (3.0 mEq/1) and very low aldosterone secretion rates (ARS) (0.9–5.8 μg/d). The hypertension and hypokalemic alkalosis were worsened by salt-loading and unchanged by treatment with spironolactone and dexamethasone. Treatment with triamterene, plus severe Na+ restriction (