Re: Hypertension with or without adrenal hyperplasia

[Guest guest]

Excellent will need to update the evolution article soon and add thisI will review and translate it so we can all understand it better.My guess is Dr. Lifton will some day win the Nobel Prize for Medicine.Clarence E. Grim, BS, MS, MD

Specializing in Primary Aldosteronism, Difficult High Blood Pressure and recent evolutionary forces on high blood pressure in populations today.On Jan 31, 2012, at 01:22 PM, Study Circle <studycircle@...> wrote:

Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5Ute I. Scholl, Carol -, Peng Yue, Grekin, J. Wyatt, J. Dillon, Couch, K. Hammer, Frances L. Harley, Anita Farhi, Wen-Hui Wang, and P. LiftonPNAS. published 30 January 2012, 10.1073/pnas.1121407109 [Abstract] [PDF]AbstractWe 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.

[Guest guest]

Thanks Dr. Grim, I was about to ask Max if he had the english version!

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> > 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.

> >

> >

> >

> >

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