Scientists at Yale University have identified mutations in the same but completely unexpected gene that may explain the severe hypertension caused by both aldosterone-producing adrenal adenomas (APAs) and a rare familial form of the disease. The researchers say their results suggest that the mutations lead to loss of potassium channel selectivity in constitutive cell proliferation and hormone production.
The results are published in Science in a paper titled "K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension."
Endocrine tumors such as APAs demonstrate constitutive hormone production and unrestrained cell proliferation. The mechanisms linking these events, however, had previously not been identified, explains senior author Richard Lifton, Ph.D., Sterling professor and chair of the department of genetics, professor of internal medicine at Yale University.
To identify a genetic link to these features Dr. Lifton’s team sequenced all the genes from a number of APAs and compared them with patients’ normal DNA. The analyses pinpointed two recurrent somatic mutations in and near the selectivity filter of the potassium channel KCNJ5, which were present in 8 of 22 human APAs studied. Both mutations produced increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells leads to calcium entry, the signal for aldosterone production and cell proliferation, the authors note.
Interestingly, additional studies identified an inherited KCNJ5 mutation that led to increased sodium conductance in an inherited form of severe aldosteronism and massive bilateral adrenal hyperplasia.
Dr. Lifton claims the work highlights the value of whole exome sequencing rather than just focusing on a few suspect gene targets. “This gene was not on anybody’s list to sequence in an investigation of this disease,” he states. “We really hit the jackpot.”