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March 10, 2014
Enzyme Linked to Severe Form of Cushing’s Syndrome
Scientists identified genetic alterations that contribute to a severe form of Cushing’s syndrome. The finding suggests new approaches to treating this rare but serious disorder.
Cushing’s syndrome results when the body’s tissues are exposed over time to too much of the stress hormone cortisol. Symptoms may include high blood pressure, muscle weakness, severe fatigue, high blood glucose, and osteoporosis. The syndrome can be caused by certain medicines or, less often, by noncancerous or cancerous tumors.
Cortisol-producing adrenal adenomas are one cause of Cushing’s syndrome. Adrenal adenomas are non-cancerous (benign) tumors that grow on one of the body’s adrenal glands, located atop each kidney. The tumors can develop at any age but most often occur in people between the ages of 40 and 60. These fairly common tumors typically cause no complications, but can sometimes cause severe problems.
To understand the molecular basis of Cushing’s syndrome, researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined the DNA of patients with a rare form of Cushing's syndrome that affects children and young adults. This form is characterized by non-cancerous growths on both adrenal glands. The researchers found duplications of the genomic region containing the PRKACA gene in tissue samples. The duplications were present in all of the patients’ cells, not just in tumor tissue, and so were likely hereditary.
PRKACA codes for a subunit of the enzyme cyclic AMP–dependent protein kinase (protein kinase A, or PKA). This enzyme has many functions in the metabolism of the cell. The investigators had previously found mutations in another gene, PRKAR1A, in a similar form of Cushing's syndrome. PRKAR1A is known to regulate PRKACA. Thus, the new finding confirmed the role of this signaling pathway in Cushing's syndrome.
At the same time, a team of international collaborators was examining the exomes of tumor specimens from 10 patients with cortisol-producing adrenal adenomas, which cause the more common, non-hereditary form of Cushing's syndrome, mostly in adults. The exome is the complete set of protein-coding regions in the genome. While it represents little more than 1% of the genome, the exome harbors most disease-causing mutations. These investigators also found defects in PRKACA.
The 2 teams worked together to examine PRKACA in another 171 patients. They found that 37% of Cushing’s patients with adrenal adenomas had mutations in the PRKACA gene. Mutant PRKACA genes were found only in tumor cells, not in other cells of the body. This shows that the mutations likely arose spontaneously in adrenal tissue.
Lab experiments with the patient samples showed that both the spontaneous mutations and the duplications led to increases in PKA enzyme activity. The results were published online on February 26, 2014, in the New England Journal of Medicine.
“The mutations we identified appear to give rise to one of the most common kinds of adrenal tumors seen in Cushing’s syndrome,” says Dr. Constantine Stratakis of NICHD, one of the study’s co-first authors. “The discovery suggests a clear path forward for investigating medications that might block the production of excess cortisol.”
In a correspondence in the same journal, Stratakis and researchers in Italy reported that a mutation in a gene coding for another portion of PKA appears to be responsible for Carney complex in a patient. Carney complex is a rare disease that causes multiple tumors and is also characterized by increased cortisol levels. Further study of this pathway will lead to more insights into these and potentially other conditions.
References: Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome. Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. N Engl J Med. 2014 Feb 26. [Epub ahead of print]. PMID: 24571724.
Funding: NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); European Commission Seventh Framework Program; Wilhelm Sander-Stiftung; Else Kröner-Fresenius-Stiftung; Bundesministerium für Bildung und Forschung; COMETE Network; Institut National du Cancer Recherche Translationelle; INSERM; Conny-Maeva Charitable Foundation; European Research Council; Deutsche Forschungsgemeinschaft; and Fondazione Telethon 2010.