Re: Re: Hypertension with or without adrenal hyperplasia

[Guest guest]

Max,

Stellar article that explains some of my questions, now that I am part of the club. When I first got involved and after reading Dr. Grim's Evolution article, my initial questions were: 1) why do some people form adenomas and others do not, 2) is a mutation the underlying cause of hyperplasia/adenomas 3) if one has the mutation, are they more likely to form additional adenomas, 4) what is the percentage of patients with recurring adenomas.

According to this article, the cell mutations are at the root of both adenomas and adrenal hyperplasia, which begs the question; are adrenal adenectomies wise given the likelihood of subsequent adenomas forming secondary to G151R mutation? Had I had the group's information when my first adenoma was found incidentally and had I pursued surgical intervention, it would have been pointless because within 10 years the remaining unaffected gland formed an adenoma. To my way of thinking, and for this reason, medical management makes far more sense.

Regarding the G151R and G151E mutations, and in Mendelian-speak, G151E appears to be a heterozygous genotype (incomplete dominance) not unlike the difference between sickle cell trait v. full blown sickle cell. Interesting also, that the more cell-lethal form (G151E) does the least damage... sort of a self-limiting mutation.

Great, great reading. Thank you.

Barbara

Re: Hypertension with or without adrenal hyperplasia

Thanks Dr. Grim, I was about to ask Max if he had the english version!> > > Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5> > Ute I. Scholl, Carol -, Peng Yue, Grekin, J. Wyatt, J. Dillon, Couch, K. Hammer, Frances L. Harley, Anita Farhi, Wen-Hui Wang, and P. Lifton> > PNAS. published 30 January 2012, 10.1073/pnas.1121407109 [Abstract] [PDF]> >> > Abstract> >> > We recently implicated two recurrent somatic mutations in an adrenal potassium channel, KCNJ5, as a cause of aldosterone-producing adrenal adenomas (APAs) and one inherited KCNJ5 mutation in a Mendelian form of early severe hypertension with massive adrenal hyperplasia. The mutations identified all altered the channel selectivity filter, producing increased Na+ conductance and membrane depolarization, the signal for aldosterone production and proliferation of adrenal glomerulosa cells. We report herein members of four kindreds with early onset primary aldosteronism of unknown cause. Sequencing of KCNJ5 revealed that affected members of two kindreds had KCNJ5G151R mutations, identical to one of the prevalent recurrent mutations in APAs. These individuals had severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control. Affected members of the other two kindreds had KCNJ5G151E mutations, which are not seen in APAs. These subjects had easily controlled hypertension and no evidence of hyperplasia. Surprisingly, electrophysiology of channels expressed in 293T cells demonstrated that KCNJ5G151E was the more extreme mutation, producing a much larger Na+ conductance than KCNJ5G151R, resulting in rapid Na+-dependent cell lethality. We infer that this increased lethality limits adrenocortical cell mass and the severity of aldosteronism in vivo, accounting for the milder phenotype among these patients. These findings demonstrate striking variations in phenotypes and clinical outcome resulting from different mutations of the same amino acid in KCNJ5 and have implications for the diagnosis and pathogenesis of primary aldosteronism with and without adrenal hyperplasia.> >> > > >> >>