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.


%d bloggers like this: