U.S. Department of Health and Human Services

Gene Mutations Linked to Hypertension

Scientists have identified mutations in two genes that play a role in the regulation of blood pressure and salt balance in a rare, heritable disease that causes high blood pressure (hypertension), a leading cause of chronic kidney disease and kidney failure. The researchers were studying a rare, inherited form of hypertension called pseudohypoaldosteronism type II, or PHAII. They analyzed genetic samples from 41 families with PHAII and identified mutations in either the KLHL3 or CUL3 genes in most. The proteins encoded by these genes, KLHL3 and CUL3, come together in kidney cells as part of a complex that targets other proteins for breakdown and recycling or other processes. The scientists hypothesize that these mutations inhibit this function of KLHL3 and CUL3, thereby disrupting normal cellular processes. The researchers also noted that the hypertension associated with PHAII can be successfully treated with drugs that promote increased fluid excretion by acting on a protein that regulates the absorption of sodium and chloride in the kidney—and that the KLHL3 and CUL3 genes are expressed in the same region of the kidney as the drug-regulated protein. 
 
This finding suggests that KLHL3 and CUL3 may be involved in helping to maintain fluid and salt balance by regulating how much fluid is retained by the kidneys’ filtering system and how much is excreted in urine. A fuller understanding of the roles these proteins play in blood pressure maintenance and fluid and salt regulation in PHAII will provide further insight into the regulation of this delicate balance in these patients. It may also identify novel targets for the treatment of hypertension arising from other causes in the general population.

Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482: 98-102, 2012.​