Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease, is an inherited disorder in which the formation of multiple renal cysts leads to kidney failure. Cysts can also form in the liver in ADPKD, which is the most common potentially life-threatening genetic disorder worldwide, affecting some 12 million people. There is no cure, and the only effective treatments are dialysis and kidney transplantation.

For more than a decade, scientists have known that mutations in a gene known as PKD1 are associated with ADPKD, but new research led by Stefan Somlo, M.D., the C.N.H. Long Professor of Medicine, professor of genetics, and chief of the Section of Nephrology, shows that polycystin-1 (PC1), the protein product of PKD1, is a central player in a five-gene network that underlies not only ADPKD, but two other polycystic diseases as well.

In the June 19 issue of Nature Genetics, a team led by Somlo, along with Craig M. Crews, Ph.D., professor of molecular, cellular, and developmental biology, professor of chemistry, and professor of pharmacology, reports that knocking out the two genes involved in polycystic liver disease also decreased levels of functional PC1, and that the severity of polycystic disease was directly correlated with the genetic “dosage” of PC1—increasing expression ofPKD1 dampened cyst formation.

In addition, low levels of PC1 promoted cyst formation in ARPKD, a less common recessive form of polycystic kidney disease. “We found that these conditions are not the result of an all-or-nothing phenomenon,” says Somlo. “The less PKD1 is expressed, the more cysts develop. Conversely, expressing more PKD1 can slow the process.”

The genes mutated in isolated human polycystic liver disease regulate quality control in protein production. When they are compromised, cellular trash collectors called proteasomes take up the slack, cleaning up improperly processed proteins and probably degrading PC1 in the process. When the researchers administered drugs that inhibit proteasomes—some of which have shown promise as cancer treatments—PC1 levels rose and cyst formation decreased. “The data suggest the exciting possibility that targeting the activity of PKD1 may be beneficial for treatment of isolated polycystic liver disease, childhood recessive polycystic kidney disease, and even a subset of adult ADPKD,” says Somlo.

Carolyn W. Slayman, Ph.D., Sterling Professor of Genetics and deputy dean for academic and scientific affairs, says, “Steve Somlo’s lab has been at the forefront of PKD research for many years, and this new paper makes an important contribution by showing the interactions among five genes in cyst formation.”