Gayed: Lifton 161 Figure 2. Schematic description of the gene fusion event which results in the constitutive production of the hormone aldosterone. (Courtesy of Dr. Richard P. Lifton) Markers in proximity to a disease gene are inherited with it, while distant markers show weak or no co-inheritance with the gene. Ge- netic maps display this information as repre- sentations of chromosomes, their genes, and the relative distances between specific gene loci (Figure 1). Presumably, affected mem- bers of a family share the same mutation and, thus, exhibit a shared genetic pattern that can be elucidated by sequencing methods. Using sequenced DNA fragments, geneticists can search the Human Genome Project to iden- tify and home in on candidate regions likely to harbor the disease gene of interest. In 1996, for example, the Lifton lab published a study in which it used the known sequence of a suspected sodium channel to identify genotypic variations among healthy individuals and individuals suffering from pseudohypoaldosteronism (PHA†) type 1. PHA is a potentially fatal dis- ease marked by profound hypotension de- spite abnormally high levels of circulating aldosterone, a steroid hormone that normally increases blood pressure [6]. As Lifton pre- dicted, affected patients were found to be homozygous for a mutation that results in the absence of the epithelial sodium channel (ENaC), the primary channel by which the kidney reabsorbs sodium. In another study, Lifton examined gluco- corticoid-remediable aldosteronism (GRA), which led to the discovery of a novel protein caused by the fusion of two separate genes, one encoding aldosterone synthase and the other encoding 11-beta hydroxylase (Figure 2). In GRA, the resultant chimeric protein ex- hibits constitutive aldosterone synthase activ- ity and, consequently, causes overproduction of aldosterone, leading to hypertension [3]. Lifton’s group used a kindred to establish complete linkage to the 11-beta hydroxylase locus. Again exploiting known genomic data, the group constructed various gene fragments to demonstrate the existence of the fusion protein by single-strand conformational poly- morphism (SSCP). In SSCP, one strand of DNA is amplified and run on a gel; differing secondary structures, due to various muta- tions, cause different bands to appear, which subsequently can be sequenced. In contrast to GRA, Liddle syndrome is marked clinically by hypertension in the ab- sence of elevated aldosterone levels. In its study of Liddle syndrome, the Lifton group mapped the phenotype to the gamma-ENaC gene subunit and sequenced it to confirm a suspected premature-stop mutation, distinct from the mutation observed in PHA patients [4]. The group analyzed a series of missense mutations in an oocyte system to confirm the role of this mutation in the pathogenesis of Liddle syndrome. The mutation, the group explains, prevents the channel’s clearance from the cell surface by causing truncation of the signal sequence that allows for ubiquitin-