Brenner Lectureship to Cover Mutations that Produce Aldosteronism

Richard P. Lifton

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Research showing that somatic mutations in a gene encoding a potassium channel lead to 40 percent of aldosterone-producing adenomas in the adrenal gland, a common cause of severe hypertension worldwide, will be the subject of the Barry M. Brenner Endowed Lectureship on Thursday, Nov. 1, at 2 p.m. Richard P. Lifton, MD, PhD, will speak on “Mutations in the K+ Channel KCNJ5 Produce Primary Aldosteronism.”

Dr. Lifton is Sterling Professor of Genetics and Internal Medicine, chair of the genetics department, executive director of the Yale Center for Genome Analysis, and investigator at the Howard Hughes Medical Institute at Yale University School of Medicine in New Haven, CT. Dr. Lifton completed his clinical training in internal medicine at Brigham and Women’s Hospital in Boston, served as chief medical resident there, and continued on the faculty at Harvard Medical School before being recruited to Yale in 1993.

Dr. Lifton’s team used a DNA sequencing strategy called whole exome sequencing to sequence all 23,000 human genes in DNA from adrenal adenomas from four patients. They compared those sequences to each patient’s own blood-cell DNA, searching for mutations that had occurred somatically in the tumors. They found very few protein-altering somatic mutations, only about two per tumor. However, a gene encoding the KCNJ5 potassium channel was mutated twice. When the researchers studied other aldosterone-producing adenomas, they found one of the two mutations in KCNJ5 present in nearly 40 percent of them. These mutations alter the selectivity filter of the channel, allowing the passage of sodium into the cells. The resulting cell depolarization leads to increased intracellular calcium, the signal for aldosterone secretion and cell proliferation.

Dr. Lifton says that these findings reveal a surprisingly simple biology for the adrenal tumors and raise the possibility of developing a screening test to identify patients with these tumors by finding one of these two mutations in cells or tumor DNA in the blood.

Dr. Lifton has been a pioneer in using human genetics and genomics to identify more than 35 disease genes involved in key pathways underlying common diseases, including hypertension, myocardial infarction, osteoporosis, cerebral hemorrhage, congenital heart disease, and neoplasia. In the case of hypertension, these studies have led to new approaches to treatment and prevention strategies for the general population. His group recently developed a method for rapidly and inexpensively sequencing all the genes in the genome that is being widely used for disease gene discovery and clinical diagnosis.

Dr. Lifton is an elected member of the National Academy of Sciences and the Institute of Medicine. He chairs the scientific advisory board of Merck Pharmaceuticals and is a member of the governing councils of the Institute of Medicine, Association of American Physicians, and Coalition for the Life Sciences.

He has received the highest scientific awards of the American Society of Nephrology, Council for High Blood Pressure Research, American Society of Hypertension, American Heart Association, International Society of Hypertension, and International Society of Nephrology. He received the Wiley Prize for Biomedical Sciences in 2008.

Notes

[1] ASN gratefully acknowledges Monarch Pharmaceuticals for support of the Barry M. Brenner Endowed Lectureship.

October-November 2012 (Vol. 4, Number 10 & 11)