Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.

@article{Beuschlein2014ConstitutiveAO,
  title={Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.},
  author={F. Beuschlein and M. Fassnacht and G. Assi{\'e} and D. Calebiro and C. Stratakis and A. O{\ss}wald and C. Ronchi and T. Wieland and S. Sbiera and F. Faucz and K. Schaak and Anett Schmittfull and T. Schwarzmayr and O. Barreau and D. Vezzosi and M. Rizk-Rabin and U. Zabel and E. Szarek and P. Salpea and A. Forlino and A. Vetro and O. Zuffardi and C. Kisker and S. Diener and T. Meitinger and M. Lohse and M. Reincke and J. Bertherat and T. Strom and B. Allolio},
  journal={The New England journal of medicine},
  year={2014},
  volume={370 11},
  pages={
          1019-28
        }
}
BACKGROUND Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35… Expand
Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome
TLDR
A hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), is reported in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing’s syndrome, providing insights into the diagnosis and therapeutics of this syndrome. Expand
Pathogenesis of benign unilateral adrenocortical tumors: focus on cAMP/PKA pathway.
TLDR
Recent findings in the pathogenesis of benign adrenocortical tumors with a particular focus on the cAMP/PKA signaling pathway are summarized. Expand
Protein kinase A defects and cortisol-producing adrenal tumors
TLDR
Somatic PRKACA mutations have been found in up to 50% of patients with adrenal adenomas and are expected to improve the understanding of how PKA defects lead to Cushing syndrome and may spearhead the development of new, molecularly designed therapies. Expand
cAMP signaling in cortisol-producing adrenal adenoma.
TLDR
The role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisol-producing adrenocortsical adenomas will be summarized, with particular focus on recent developments. Expand
Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors
TLDR
Different mechanisms underlying adrenal cortisol-producing tumors are defined, including PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. Expand
A genetic and molecular update on adrenocortical causes of Cushing syndrome
TLDR
The presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia and Cushing syndrome is discussed, with a focus on genetic findings in the past few years. Expand
PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases.
TLDR
Somatic mutations in PRKACA(L206R) is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion, and was associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutants. Expand
Alterations in Protein Kinase A Substrate Specificity as a Potential Cause of Cushing Syndrome.
TLDR
Investigating a large panel of PRKACA mutations, including all those identified so far in Cushing syndrome, it is found that not all mutations interfere with the binding of regulatory (R) subunits as previously hypothesized, which suggests that in addition to hampering binding to R subunits, PRkACA mutations act by altering PKA substrate specificity. Expand
PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors
TLDR
The current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and the understanding of PKA's role in adrenOCortical lesions are summarized and potential therapeutic advances that can be made are discussed. Expand
Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas.
TLDR
It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out. Expand
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