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NIH Researchers Identify Mutation Linked to Severe Form of Cushing’s Syndrome

Published: Friday, February 28, 2014
Last Updated: Friday, February 28, 2014
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Mutation in related gene found in patient with Carney Complex.

Mutations in a gene containing part of the information needed to make an enzyme that provides energy for governing basic cell functions appear to contribute to a severe form of Cushing’s syndrome, according to researchers at the National Institutes of Health and nine European research institutions.

Cushing’s syndrome ( results when the body is exposed to too much of the stress hormone cortisol. The syndrome may result when the body itself produces excess cortisol, causing symptoms that may include high blood pressure, muscle weakness or osteoporosis.

The study was published online in the New England Journal of Medicine. In a letter to the editor of the same journal, members of the NIH research team and researchers in Italy reported that a mutation in another gene containing information needed to make yet another portion of the enzyme appears to be central to Carney Complex (, a rare disease that causes multiple tumors and which is characterized by increased cortisone levels.

For the study on Cushing’s syndrome, the researchers examined tissue from patients having a subtype of Cushing’s syndrome, in which the source of the excess cortisol is a noncancerous tumor confined to only one of the body’ two adrenal glands. The researcher examined samples from nearly 200 such adrenal gland tumors. They found that 37 percent contained a mutation in the gene known as PRKACA.

“The mutation we identified appears to give rise to one of the most common kinds of adrenal tumors seen in Cushing’s syndrome,” said study co- first author Constantine Stratakis, M.D., D.Sc., director of the Division of Intramural Research and head of the Program on Developmental Endocrinology and Genetics at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute that took part in the study. “The discovery suggests a clear path forward for investigating medications that might block the production of excess cortisol.”

The PRKACA gene contains the information needed to make a portion, or subunit, of the PKA (protein kinase A) enzyme. The enzyme is involved in numerous chemical reactions in the cell.

For these patients, the mutant PRKACA gene was found only in the tumor cells, and not in other cells of the body. Because the gene was not found in other cells of the body, the mutation likely arose spontaneously in the adrenal tissue.

The researchers also examined tissue from patients who had non-cancerous growths on both adrenal glands. In samples from these patients, the researchers found an extra copy of the PRKACA gene. This extra copy, they noted, was present in all of the patients’ cells, and was not limited to the tumor tissue. Because the mutation was found in all the cells of the body, it was likely hereditary.

However, in both the cases involving the spontaneous mutation and the inherited mutation, the activity of the PKA enzyme was increased.

“The mutation appears to spur the activity of this enzyme, Dr. Stratakis said. “The result appears to be an increase in cell growth and division in adrenal tissue, and an overproduction of cortisol.”

Dr. Stratakis collaborated with the other co-first authors, including Felix Beuschlein, M.D., of the Ludwig-Maximilians-University, in Munich, Germany; Martin Fassnacht, M.D., of Ludwig-Maximilians-University and the University of Wurtzburg, in Wurtzburg, Germany; Guillaume Assie, M.D., Ph.D., of the Paris Descartes University and Cochin Hospital, in Paris; Davide Calebiro, M.D., of the University of Wurtzburg; and 25 other researchers at the NICHD and institutions in France, Germany and Italy.

In a letter to the editor of the same issue of the New England Journal of Medicine, Orsetta Zuffardi of the University of Pavia, in Pavia, Italy and Dr. Stratakis and other colleagues in Italy and at the NIH discovered that a patient with Carney Complex, who had a tumor in the pituitary gland and elevated growth hormone, had an extra copy of the PRKACB gene. This gene codes for another subunit of Protein Kinase A. In addition to elevated growth hormone levels, people with Carney Complex often have skin spots and increased risk of tumors in the pituitary, adrenals as well as other parts of the body.

“It’s likely that the extra copy of this gene also increases the activity of protein kinase A, essentially setting the stage for increased cell proliferation and higher production of hormones,” Dr. Stratakis said.

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