Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5.

Proc Natl Acad Sci U S A. 2012 Jan 30;
Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A, Wang WH, Lifton RP

We recently implicated two memorable somatic mutations in an adrenal potassium channel, KCNJ5, as a cause of aldosterone-producing adrenal adenomas (APAs) as well as one inherited KCNJ5 turn in a Mendelian form of early severe hypertension with massive adrenal hyperplasia. The mutations identified all altered a channel selectivity filter, producing increased Na(+) conductance as well as membrane depolarization, a signal for aldosterone production as well as proliferation of adrenal glomerulosa cells. We inform herein members of four kindreds with early onset primary aldosteronism of unknown cause. Sequencing of KCNJ5 suggested that affected members of two kindreds had KCNJ5(G151R) mutations, matching to one of a prevalent memorable mutations in APAs. These individuals had severe progressive aldosteronism as well as hyperplasia requiring bilateral adrenalectomy in childhood for blood vigour control. Affected members of a other two kindreds had KCNJ5(G151E) mutations, that are not seen in APAs. These subjects had simply controlled hypertension as well as no evidence of hyperplasia. Surprisingly, electrophysiology of channels expressed in 293T cells demonstrated that KCNJ5(G151E) was a some-more impassioned mutation, producing a much larger Na(+) conductance than KCNJ5(G151R), resulting in rapid Na(+)-dependent cell lethality. We infer that this increased malignancy limits adrenocortical cell mass as well as a astringency of aldosteronism in vivo, accounting for a milder phenotype among these patients. These findings demonstrate striking variations in phenotypes as well as clinical outcome resulting from opposite mutations of a same amino acid in KCNJ5 as well as have implications for a diagnosis as well as pathogenesis of primary aldosteronism with as well as without adrenal hyperplasia.

healthcare jobs