Edited by: Steven Benowitz
R.A. Shimkets, D.G. Warnock, C.M. Bositis, C. Nelson-Williams, J.H. Hansson, M. Schambelan, J.R. Gill, S. Ulick, R.V. Milora, J.W. Findling, C.M. Canessa, B.C. Rossier, R.P. Lifton, "Liddle's syndrome: Heritable human hypertension caused by mutations of the beta subunit of the epithelial sodium channel," Cell, 79:407-14, 1994. (Cited in more than 70 papers as of October 1996)
Comments by Richard A. Shimkets, Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine.
LOOKING AHEAD: Yale's Richard Shimkets questions how genetic mutations caused hypertension.
Lifton, an associate professor of medicine and genetics and a Howard Hughes Medical Institute investigator, along with Richard Shimkets, a graduate student in genetics at Yale's School of Medicine, originally examined the inheritance pattern of hypertension in a large family with Liddle's syndrome. The researchers identified a mutation in the beta subunit of the epithelial sodium channel in every family member who had the disease. Subsequent studies in four other families indicated similar mutations in all of these patients as well.
"The linked region contained a gene encoding a sodium channel subunit, and we know that sodium is important in regulating blood pressure," says Shimkets. They discovered that the gene was mutated and that in different families with Liddle's syndrome, such mutations removed the same part of the channel subunit in each case. As a result, this gene mutation causes too much sodium to be reabsorbed by the kidney, expanding blood volume and leading to hypertension.
In a subsequent paper (J.H. Hansson et al., Nature Genetics, 11:76-82, 1995), Lifton's team found that a similar mutation of the gamma subunit of the epithelial sodium channel also caused Liddle's syndrome.
GENE HUNTER: Yale geneticist Richard Lifton's laboratory found a gene behind inherited hypertension.
Shimkets points out that other mutations in this gene may alter blood pressure and may be more common, though this hasn't been proved. Determining the molecular and cellular pathways involved in this disease may help researchers better understand how other forms of hypertension arise.
In another paper (S.S. Chang et al., Nature Genetics, 12:248 53, 1996), scientists identified mutations in either the alpha or the beta subunit of the same sodium channel that caused another disease, pseudohypoaldosteronism type 1. "The mutation affects the sodium channel, but does the exact opposite," Shimkets says. "The mutated gene actually knocks out-rather than enhances-the function. There's not enough sodium reabsorbed because the sodium channels aren't functioning. "The advantage is that we found a weak link in the regulation of blood pressure, where mutations can cause disease. We're trying to find other candidates that might interact with and modify sodium channels. If you find other types of mutated genes in the pathway, they might play a role in hypertension. "Hypertension is very common," he points out, adding that "a large fraction is genetic. It's a complex illness-there could be many genes involved that might contribute to the condition."
Shimkets thinks that the Cell paper was cited so often because "it provided a clear example of how a mutation changing renal salt handling could translate into a complex trait such as hypertension." This paper has spurred investigation of other genes involved in salt handling for a role in hypertension and has been of interest to cell biologists investigating the removal of cell proteins from the cell surface.
"The next step is to determine the mechanism of how these mutations lead to increased sodium reabsorption," Shimkets reports. "It may be because of more sodium channels at the cell surface, but the mechanism is probably complex. It will be a while before the mechanism is entirely worked out."