PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia

Eur J Endocrinol. 2015 Mar 6. pii: EJE-14-1113. [Epub ahead of print]

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia – a single-center study of 60 cases.


Objective: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing’s syndrome. Recent genetic studies have identified a somatic PRKACAL206R mutation as a cause of cortisol-producing adenomas.

We aimed to compare the clinical features of lesions with PRKACA mutations to those with CTNNB1 mutations and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.

Design, patients and methods: 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. 36 patients had overt Cushing’s syndrome, the remainder were subclinical. 59 cases were adenomas (three bilateral), one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.

Results: Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8% and CTNNB1 plus GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACAL206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing’s syndrome and higher cortisol levels versus non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.

Conclusions: PRKACAL206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

[PubMed – as supplied by publisher]


Myth: “Men1 and Men2 are the only genetic causes of Cushing’s”

Myth: “Men1 and Men2 are the only genetic causes of Cushing’s”


FACT: This is a Myth. More current research has explored multiple etiologies of Cushing’s. It was once thought that heredity had no influence on the development of Cushing’s Syndrome/Disease and our knowledge was once limited in this sense. Researchers have done more work in terms of exploring genetic factors in the onset of this disease. *~Robin Ess (Cushing’s educator and advocate)

The following causes for Cushing’s have all been explored:

1. Men 1

2. Men2



5. PRKAR1A(protein kinase,cAMP-dependent, regulatory, type I, ? gene)




Genetics of adrenal diseases in 2014: Genetics improves understanding of adrenocortical tumours

2014 has seen advances in our understanding of benign and malignant tumours of the adrenal cortex, particularly in Cushing syndrome. Modern genetics has generated a flurry of data. The challenge is to give sense to them; however, the difficulties of collecting the clinical data must not be underestimated.

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  • References
  1. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 10191028 (2014).
  2. Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613617 (2014).
  3. Sato, Y. et al. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science 344, 917920 (2014).
  4. Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 344, 913917 (2014).
  5. Assié, G. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N. Engl. J. Med. 369, 21052114 (2013).
  6. Assié, G. et al. Integrated genomic characterization of adrenocortical carcinoma. Nat. Genet. 46, 607612 (2014).
  7. Beuschlein, F. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat. Genet. 45, 440444 (2013).
  8. Scholl, U. I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat. Genet. 45,10501054 (2013).
  9. Azizan, E. A. et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat. Genet. 45, 10551060 (2013).
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Mutations in PKA catalytic subunit associated with Cushing’s syndrome

1. Somatic mutations resulting in constitutive activation of PRKACA, which encodes the catalytic subunit of protein kinase A, were found in 37% of patients with Cushing’s syndrome due to an adrenal adenoma. 

2. Germline duplications of PRKACA were detected in patients with bilateral adrenal hyperplasia and overt Cushing’s syndrome. 

Study Rundown: This study found that 37% of patients with overt Cushing’s syndrome due to an adrenal adenoma have a somatic mutation in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase A (PKA), present in their tumor cells. The most commonly identified variant, Leu206Arg, results in impaired interaction between the catalytic and regulatory subunits of PKA, thereby causing constitutive activation of PKA. Additionally, a subset of patients with cortisol-producing bilateral adrenal hyperplasia harbored germline duplications of PRKACA.

This is the first study to identify an association between genetic alterations of the catalytic subunit of PKA and Cushing’s syndrome. It is significant that 37% of patients with overt Cushing’s syndrome were found to have tumors with PRKACA mutations; previous research had revealed only very rare mutations. Of note, this study did not find PRKACA mutations in any patients with subclinical Cushing’s syndrome or inactive adenomas. This suggests that Cushing’s syndrome and subclinical Cushing’s are distinct entities. Patients involved in this study were recruited from only three centers; the frequency of PRKACA mutations in Cushing’s syndrome may be different in other study populations. Further research will be needed to identify biochemical causes of overt Cushing’s syndrome in patients without PRKACA mutations.

Relevant Reading: Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing’s syndrome despite the absence of mutations in known genes

In-Depth: In this study, exome sequencing of tumor specimens from 10 patients with unilateral cortisol-producing adenomas and overt Cushing’s syndrome was performed. Eight of 10 adenomas had somatic mutations in PRKACA; 7 of these patients had the same mutation (p.Leu206Arg). Subsequently, PRKACA was sequenced in 129 additional patients with adrenal adenomas. Patients were classified as having overt Cushing’s syndrome (at least three abnormal biochemical tests or catabolic features plus two abnormal tests), subclinical Cushing’s (at least one abnormal biochemical test without catabolic signs) or as having an inactive adenoma. The Leu206Arg variant was identified in tumor tissue of 14/129 patients and all 14 had overt Cushing’s syndrome. Overall, 37% (22/59) of patients with overt Cushing’s syndrome due to an adenoma had a PRKACA mutation; in contrast, PRKACA mutations were not found in any patients with subclinical Cushing’s or an inactive adenoma. Of 35 patients with overt Cushing’s syndrome due to cortisol-secreting bilateral adrenal hyperplasia, 5 patients had copy-number gains of a region on chromosome 19p that contains PRKACA.

Analysis of holoenzyme structure revealed that the Leu206Arg mutation is located in the active-site cleft of the catalytic subunit of PKA. To evaluate the functional consequences of this mutation, cells were transfected with either nonmutant or variant C-alpha, which encodes the catalytic subunit of PKA. Investigators determined that the mutation causes constitutive activation of the catalytic subunit by impairing interaction with the regulatory subunit of PKA.


Genetic variations associated with hyperplasias, adenomas of adrenal cortex

Beuschlein F. N Engl J Med. 2014;doi:10.1056/NEJMoa1310359.

Genetic variations of the catalytic subunit of cyclic protein kinase A, or PKA, were linked to the development of bilateral adrenal hyperplasias and unilateral cortisol-producing adrenal adenomas. These effects may activate corticotropin-independent Cushing’s syndrome, according to data published in The New England Journal of Medicine.

“The current study suggests that more than one-third of cortisol-producing adenomas associated with overt Cushing’s syndrome have unique somatic mutations in PRKACA (which encodes the main catalytic subunit of PKA), resulting in constitutive PKA activation,” Felix Beuschlein, MD, of the University of Munich, and colleagues wrote.

The researchers performed an exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated their recurrent mutations in candidate genes in 171 additional patients with adrenocortical tumors, according to data.

Somatic mutations in PRKACA were discovered in eight of 10 adenomas. These somatic mutations also were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing’s syndrome; mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors, according to data.

Five of the 35 patients with cortisol-producing hyperplasias appeared to be carriers of the germline duplication of the genomic region on chromosome 19 that includes PRKACA, researchers wrote.

In vitro study data indicated that PKA catalytic subunit genetic mutations impaired inhibition by the PKA regulatory subunit, and cells from patients with germline chromosomal gains appeared to increase the protein levels of the subunit.

“Because PRKACA mediates most of the effects of inactivating PRKAR1A mutations and because mutations of PRKAR1 are associated with a variety of tumors in humans and mice, we would speculate that somatic PRKACA defects might also play a role in other forms of endocrine and nonendocrine tumors,” researchers wrote.

Disclosure: Beuschlein reports financial ties with the European Community, HRA Pharma, Novartis, Viropharma, and Wilhelm-Sander Stiftung.


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