GENETIC STUDIES OF LIDDLE'S SYNDROME

Yale University, New Haven CT

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Linked publications & trials

Abstract

The renal mineralocorticoid-sensitive, amiloride-sensitive epithelial sodium channel is thought to be a key regulator of net sodium reabsorption in humans, and is consequently a strong candidate to harbor mutations contributing to the pathogenesis of hypertension. We have recently demonstrated that Liddle's syndrome, an autosomal dominant form of human hypertension, results from mutation in the beta subunit of the epithelial sodium channel (bENaC). All mutations identified thus far introduce premature stop codons or frameshifts nto the gene, removing normal sequences from the cytoplasmic carboxy terminus of the encoded protein. Clinically, the consequence of these mutations appears to be increased activity of the channel in the absence of mineralocorticoids, permitting increased salt and water reabsorption and.resulting in a form of low renin hypertension. These findings demonstrate that mutations in this channel can indeed result in human hypertension, and provide a human model of salt-sensitive hypertension. In this grant we propose to l) Determine the spectrum of mutations causing Liddle's syndrome by study of known unrelated subjects with Liddle's syndrome. This will determine whether all patients with Liddle's syndrome have mutations in bENaC or whether there is genetic heterogeneity. 2) Identify a cohort of patients with Liddle's syndrome using genetic screening of at-risk relatives of identified cases with known mutations. This will permit description of the clinical spectrum and natural history of the disease. Linkage analysis will be used to determine the quantitative effects of inheritance of the gene on blood pressure and to determine whether factors such as inheritance at other genetic loci contribute to phenotypic variation. Features of Liddle's mutations demonstrate the existence of a previously unknown pathway by which channel activity is regulated motivating further study. We have developed a system for expression of the mutant channels in order to determine how these mutations alter channel activity. Preliminary evidence demonstrates expression of mutant channels has a marked effect on increasing net channel activity, providing the opportunity to define l) how this effect is mediated and 2) what sequences in the protein are responsible for this effect.