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Mutation Linked to Severe Form of Cushing’s Syndrome


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.


According to a paper published online in the New England Journal of Medicine (27 February 20014), 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. 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 cortisol levels.


For the study on Cushing’s syndrome, the authors 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’s two adrenal glands. When samples from nearly 200 such adrenal gland tumors were examined, it was found that 37% contained a mutation in the gene known as PRKACA. 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. According to the authors, the mutant PRKACA gene appears to give rise to one of the most common kinds of adrenal tumors seen in Cushing’s syndrome, and that the discovery suggests a clear path forward for investigating medications that might block the production of excess cortisol.


The authors also examined tissue from patients who had non-cancerous growths on both adrenal glands. In samples from these patients, an extra copy of the PRKACA gene was found. This extra copy 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, the authors concluded that 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.


In a letter to the editor of the same issue of the New England Journal of Medicine, it was reported 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. According to the authors, it is 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.


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