While pursuing the genetics of blood pressure regulation, Rick Lifton has encouraged scientists in his laboratory to follow their interests in other disorders whose secrets might yield to genetic exploration.

Kidney malfunction—end-stage renal disease, in particular—is a major problem that some team members are beginning to tackle. "If you take a broad view of big public-health problems," Lifton says, "in the last 30 years we've made substantial strides in preventing stroke by treating hypertension, and a lot of progress in lowering the incidence of heart attack by reducing smoking and cholesterol levels. And yet, the incidence of end-stage renal disease has continued to go up, doubling every 10 years. So, we've been looking around for genetic approaches to end-stage renal disease, one of the most interesting of which has been the most common form of glomerulonephritis, called IgA nephropathy."

IgA nephropathy affects up to 1 percent of the population worldwide and 100,000 people in the United States alone. It first shows up as blood in the urine, progressing to kidney-clogging deposits of the immune-related protein immunoglobulin, or IgA. Many patients develop kidney failure and need dialysis or a transplant to survive.

A number of scientists have assumed that IgA nephropathy sprang from multiple factors. But when physician Ali Gharavi, a fellow in Lifton's lab, studied the disease in 30 U.S. and Italian families, he found, surprisingly, that the disease in most of the families was attributable to a single genetic locus on chromosome 6. Gharavi reported the results in the November 2000 Nature Genetics. "This falls into the category of a disease about which we know almost nothing of its fundamental pathophysiology," Lifton says. "This finding demonstrates that genetic approaches to this disease will likely reveal its underlying biological mechanisms."

In another promising foray, Lifton has launched studies of how pH and magnesium levels are controlled in the kidneys. "Our work on magnesium has taken us in some unexpected directions," he says. "We've ended up discovering that mutations in a particular class of molecules called the claudins mediate the flux of electrolytes through a novel pathway called the paracellular pathway." The surprise, says Lifton, is that this pathway consists of selective pores in the tight junctions between cells that allow certain ions to pass between the cells but not through the cell membrane. "These aren't simple holes in the gaskets; they're highly selective and specific pores," he explains.

Working in Lifton's laboratory on a study of families with a rare magnesium-wasting disorder, Yin Lu, a physician-scientist, and Keith Choate, an M.D., Ph.D. student, have pinpointed a culprit gene named paracellin-1. This gene mediates the selective flux of magnesium across the tight junctions of a specific segment of the kidney's epithelium. The implication is that other members of the claudin family mediate the selective flux of ions, nutrients and even cells across body membranes.

In other genetic studies, lab member Murat Gunel, an assistant professor of neurosurgery, is focusing on a common neurological disorder called cavernous malformations, in which blood vessels in the brain become abnormally enlarged, causing seizures and paralysis. He is identifying genes whose mutations can cause the disease and exploring the underlying molecular mechanisms.

"All these studies represent our efforts to create an environment where young physician-scientists and postdocs can come and learn human genetics and laboratory methods and then pursue problems on their own," says Lifton. "While we certainly remain absolutely committed to our core studies of hypertension, we also believe it important to explore promising new directions. The limitation, of course, is how many we can actually juggle simultaneously."

—DM

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Reprinted from the HHMI Bulletin,
May 2001, pages 22-27.
©2001 Howard Hughes Medical Institute