162 Gayed: Lifton Figure 3. Luminal surface of distal nephron in healthy individual (top half) and patient with Liddle syndrome (bottom half). In Liddle syndrome, the signal sequence known as PPPXY is lost, which impairs the normal clearance of ENaC via clathrin-coated endocytosis. (Courtesy of Dr. Richard P. Lifton) mediated degradation (Figure 3). The pro- longed presence of ENaC results in enhanced sodium reabsorption and hypertension. One of the more recent and surprising dis- coveries of the Lifton lab, however, came in 2002 when a resequencing of genes involved in the salt-retaining pathway revealed a mutation in the mineralocorticoid receptor (MR) of a 15- year-old hypertensive boy [5]. Normally, bind- ing of aldosterone to MR causes increased salt reabsorption by enhancing the activity of ENaC. However, the mutation, which replaces a single serine residue with leucine, causes the receptor to be partially activated in the absence of aldos- terone. More interestingly, however, is that the mutation enhances the receptor’s sensitivity to progesterone and completely inverts the role the steroid has on the receptor; that is, in the pres- ence of the mutation, progesterone, which usu- ally acts as an antagonist, becomes a potent agonist. Considering that progesterone levels can increase 100-fold during gestation, this find- ing suggests the MR mutation also may be re- sponsible for the severe pregnancy-induced hypertension observed in some women. Indeed, in Lifton’s study, two female carriers of the mu- tant allele had multiple hypertensive complica- tions during each of their pregnancies [6]. Lifton also has demonstrated that salt- wasting defects, such as those seen in Gitel- man’s syndrome, result in lowered blood pressure. In a 2001 investigation, the Lifton lab studied individuals who carried zero, one, or two copies of a mutant gene encod- ing a sodium-chloride cotransporter in order to ascertain its influence on blood pressure [6]. Mutations were identified using SSCP. The group found that homozygous mutant individuals had diastolic blood pressures about 8 mm Hg lower than their wild-type and heterozygous kindred. Although no sig- nificant blood pressure differences existed between the heterozygous group and the wild-type group, members of the former consumed significantly more salt in their diet, which Lifton explains as a compensa- tory dietary preference counterbalances the mild salt-wasting defect. For as much as Lifton has accom- plished, the problem of hypertension re- mains a difficult one because the majority of hypertensive patients do not have a mutation that leads to profound physiological defects. Rather, it is more often the case these pa- tients are afflicted by subtle and varied genotypic patterns that give rise to a set of heterogeneous disease states we have grossly named “chronic hypertension.” “If there are many genes that influence [chronic hypertension] by a common path-