Dr. Gary Gibbons, Director, NHLBI:  I wanted to switch gears a bit because I know you’re a bit pleiotropic as a scientist and I know this is just one slice of some of your interests. Could you just bring us up to date on some of the other research projects that you’re excited about within your program?

Dr. Richard Lifton, Yale University:  Sure, thanks for the opportunity. One of the areas that we’ve been very interested in over the years is hypertension, which as you know well, affects a billion people worldwide and is the major contributor to stroke and heart attack, leading causes of death in the United States and worldwide. And one of the areas that we’re particularly interested in are tumors of the adrenal gland that secrete the hormone aldosterone. These are called aldosterone producing adenomas. And if you walk into a hypertension referral clinic anywhere around the world, 5% to 10% of these patients will have these tumors. 

Again, a fundamental question has been what is the underlying biology of these tumors that allows the growth of the tumor, as well as the constitutive production of the steroid hormone, aldosterone, which is the cause of hypertension in these patients. And we recently sequenced a cohort of these tumors and demonstrated, I think very surprisingly, that about 40% of these tumors from around the world in different cohorts are caused by mutations in a single potassium channel. And these mutations are actually gain-of-function mutations that change the way the channel operates. It changes the channel from only conducting potassium out of the cell to now conducting sodium, which normally can’t permeate through this channel. And sodium now, because sodium levels are high outside the cell and low inside the cell, sodium comes rushing into the cell and importantly, that causes cell depolarization. The membrane potential is changed and that’s the signal for activating a calcium channel and calcium then enters the cell. And the consequence of that is that’s the signal dose acutely, for aldosterone production and chronically, for cell proliferation.

So this is a beautiful example by which a single mutation is sufficient to cause the cardinal manifestations of these tumors – their cellular growth and also the production of this hormone, aldosterone. And the proof that this, in fact, is sufficient in the cause is they’re around patients who have this mutation not arising as a mutation in a single cell in the adrenal gland but they have these mutations in every cell in the body in the germline. And these patients have extraordinary hyperplasia of the adrenal gland and phenomenal hypertension early in life. So this is a very nice example where a single mutation is sufficient for the production of an individual tumor with biological activity.

And we think this provides opportunities for both new approaches to diagnosis of these tumors, as well as their treatment.

Dr. Gibbons:  Wow, that’s fascinating. So would that work as a potential pharmacologic intervention prior to discovery of a tumor?

Dr. Lifton:  Right. So that’s a great question. So right now, if you have aldosteronism, high levels of aldosterone, which were found in about 10% of patients referred for hypertension, the diagnostic path to recognizing that you have one of these tumors is quite difficult and involves an invasive production that requires threading a catheter up through into the adrenal vein and sampling blood from the left and the right adrenal vein and looking for aldosterone production in both. We imagine that we might be able to diagnose these tumors more readily by alternative approaches. And one would be because these mutations are so distinctive for these tumors and they occur at only two predominant positions in almost all of these tumors, we might be able to develop highly sensitive assays for these mutations that we would be able to recognize in blood samples alone, and that would be an easy diagnostic test.

A second possibility would be we believe that the mutated channels have a different structure than the normal channel because they allow sodium to pass rather than just potassium, and that we might be able to identify small molecules that selectively inhibit the mutant channel and not the normal channel. These could be both diagnostics and therapeutics. So for example, you could have a patient in clinic in whom this disease was on the differential diagnosis list and give them such a drug and see whether the aldosterone levels dropped in a short-term course, a couple of days of treatment. Then that could either lead to further efforts to find the tumor and remove it surgically or simply maintain the patient on such a drug long-term.

But clearly, it’s surprising that the biology of these tumors appears to be so simple and it also has implications for other hormone producing tumors, of which there are a number. 

Dr. Gibbons:  This is fascinating. I could talk to you all day but I know we don’t have it all. One quick question on the aldosterone. As you know, there’s been a finding that African Americans seem to have more hyperaldosteronism. Do you have any data related to the frequencies of these variants by ancestry?

Dr. Lifton:  These particular mutations do not appear to be prevalent in any population around the world, likely because they are so deleterious they cause such rip-roaring hypertension. But they do pose the question as to why different groups of different ancestry appear to have different basal rates of aldosterone production. And I think it is particularly intriguing that populations that are ancestral from, recently, ancestral from Africa tend to make more aldosterone. Of course, this may relate to our ancestral relationship between salt and volume homeostasis and blood pressure. As you well know, sub Saharan Africa was an extremely salt poor environment and so it’s not hard to imagine that we’ve revved up all of our salt retaining pathways in that environment. And now that we are in a salt rich environment where the average American is eating 10 grams of sodium chloride a day, those same genes might be contributing to the development of hypertension.
SEGMENT 4: Dr. Gibbons and Dr. Lifton Q&A Transcript
May 29, 2013




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