PRKACA – Cushing syndrome

Cushing syndrome (CS) is characterized by cortisol excess leading to metabolic derangements, hypertension, and osteoporosis. Corticotropin-independent CS is commonly caused by benign cortisol-secreting adrenal adenomas (CPAs). The protein kinase A catalytic subunit alpha, encoded by PRKACA (HGNC:9380), has emerged as a central driver of cortisol overproduction in these tumors. Genetic and functional studies over the past decade have established a robust link between somatic PRKACA mutations and autonomous adrenal cortisol secretion.

Somatic hotspot mutations in PRKACA cluster at codon 206. The recurrent c.617T>G (p.Leu206Arg) alteration was found in 27/87 CPAs (31%) in whole-exome and RNA sequencing analyses of adrenal tumors ([PMID:24700472]). In a cohort of 59 unilateral cortisol-producing adenomas, 22 (37%) harbored the same variant ([PMID:24571724]), and in a multicenter study of 64 CS patients, 22 (34%) carried p.Leu206Arg ([PMID:25057884]). Overall, somatic PRKACA p.Leu206Arg has been reported in >100 unrelated adenoma patients, firmly establishing its recurrence and specificity for overt CS.

Beyond p.Leu206Arg, other PRKACA alterations include small insertions and duplications in exon 7, such as c.595_596insCAC (p.Thr198_Leu199insSer), identified in 8/10 sequenced tumors ([PMID:24571724]). Somatic copy-number gains of the PRKACA locus have also been reported in bilateral adrenal hyperplasias, with germline duplications or triplications leading to early-onset CS in affected families ([PMID:24571724]). The variant spectrum underscores the critical sensitivity of the PKA catalytic core to activating genetic events in adrenal tumorigenesis.

Functional characterization demonstrates that p.Leu206Arg disrupts binding to the regulatory subunit PRKAR1A, resulting in constitutive, cAMP-independent PKA activation. In vitro kinase assays revealed impaired inhibition by PRKAR1A and elevated basal PKA activity in mutant cells ([PMID:24855271]). Quantitative phosphoproteomic profiling further showed that p.Leu206Arg and other CS-associated variants alter substrate specificity, notably hyperphosphorylating histone H1.4 at Ser36, which promotes mitosis ([PMID:30615103]).

Structural and biophysical studies indicate that the L205R mutation (homologous to L206R in PRKACA) rewires the PKA allosteric network. NMR spectroscopy and molecular dynamics simulations revealed loss of cooperativity between nucleotide and substrate binding and the emergence of novel substrate interactions, explaining both deregulated activity and altered signaling outputs in tumor cells ([PMID:31489371]).

Clinically, patients with PRKACA-mutant CPAs present with overt CS, smaller adenoma size, and higher cortisol levels compared to non-mutant or CTNNB1-mutant tumors ([PMID:24571724]). Germline PRKACA amplifications manifest as bilateral adrenal hyperplasias with variable nodularity and childhood or adult-onset CS, supporting dosage sensitivity of PRKACA in adrenal cortex growth and steroidogenesis.

Collectively, the extensive genetic and functional data fulfill the highest ClinGen criteria for clinical validity, establishing a definitive association between somatic PRKACA mutations and corticotropin-independent Cushing syndrome. Testing for PRKACA variants, particularly c.617T>G (p.Leu206Arg), is of high diagnostic and potential therapeutic relevance in patients with adrenal CS.

References

• Science • 2014 • Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. PMID:24855271
• The New England Journal of Medicine • 2014 • Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. PMID:24571724
• Nature Genetics • 2014 • Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. PMID:24747643
• The Journal of Clinical Endocrinology and Metabolism • 2014 • Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study. PMID:25057884
• Endocrinology • 2019 • Alterations in Protein Kinase A Substrate Specificity as a Potential Cause of Cushing Syndrome. PMID:30615103
• Science Advances • 2019 • Cushing's syndrome driver mutation disrupts protein kinase A allosteric network, altering both regulation and substrate specificity. PMID:31489371

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