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Activating Hotspot L205R Mutation in PRKACA and Adrenal Cushing's Syndrome

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Science  03 Apr 2014:
1249480
DOI: 10.1126/science.1249480

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Abstract

Adrenal Cushing’s syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which lead to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), and adrenocortical oncocytoma (ADO). We identified a hotspot in the PRKACA gene with a c.T617G/p.L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of total 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of PKA catalytic subunit, promoted PKA substrates phosphorylation and target genes expression. Moreover, we discovered recurrently mutated DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing’s syndrome.

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