Clinical characteristics of PRKACA mutations in Chinese patients with adrenal lesions: a single‐centre study

Abstract

PRKACA mutations are present in CPAs and bilateral adrenal macronodular hyperplasia. PRKACA mutation is associated with more severe autonomous cortisol secretion.

Clinical Characteristics of Aldosterone- and Cortisol-Coproducing Adrenal Adenoma in Primary Aldosteronism

“…Bidirectional Sanger sequencing was performed for targeted mutation detection in the KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and PRKACA genes using DNA extracted from the tumor tissues of the 22 A/CPA patients. The DNA extraction and sequencing were performed as previously described [ 18 ]. The sequencing primers are shown in Supplementary Table 1 .…”

PRKACA Mutations in Adrenal Adenomas: Genotype/Phenotype Correlations

“…Functional studies did not indicate a relevant role of PKA activation and, accordingly, no clear clinical or hormonal characteristics suggesting the presence of hypercortisolism were present in this patient. In the other 3 independent series available in the literature [6][7][8], no mutations in the PRKACA hot spot region were identified. More recently, a case report has shown the occurrence of 2 different adenomas harboring independently a PRKACA mutation (p.L206R) and a novel KCNJ5 variant (p.T148I/T149S) [37].…”

“…Additionally, novel somatic mutations in PRKACA have been discovered in the first follow-up cohort including 64 adrenocortical adenomas associated with Cushing's syndrome [5]. One of those, p.C200_G201insV has also been identified in 2 additional cases in a recent series published by Li and colleagues [8]. Moreover, in a very recent paper describing the somatic molecular events identified by exome sequencing, occurring in a large series of adrenocortical adenomas, 3 additional somatic mutations have been detected in PRKACA, in positions other than the known hotspot region [10].…”

“…Considering the activating effects of somatic PRKACA mutations on the Cα subunit and the regulatory role of this subunit on several downstream targets involved in cortisol secretion, it is obvious to expect deleterious effects of those mutations on the steroido-genic profile. In fact, subjects carrying tumors with somatic Cα mutations were shown to exhibit a more severe hormonal phenotype than those without such mutations in the majority of studies, on the basis of increased cortisol levels after dexamethasone suppression test, higher midnight serum or salivary cortisol, and 24-h urinary free cortisol [1,3,5,7,8].…”

“…Since 2014, our collaborative group and others have discovered and characterized the most frequent genetic event causing unilateral adrenal Cushing's syndrome: in a considerable proportion of sporadic cortisol-producing adrenal tumors, the mutations in the gene encoding the catalytic subunit α (Cα) of protein kinase A (PKA) (PRKACA) were identified [1][2][3][4]. Through these initial and further follow-up studies, PRKACA somatic mutations were confirmed as a common genetic event in a large proportion of patients, with a clear pathogenetic role in inducing cortisol production [5][6][7][8]. These somatic mutations have been found in a hot-spot region of PRKACA, leading to different amino acid substitutions.…”