Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome

Science. 2014 May 23;344(6186):913-7. doi: 10.1126/science.1249480. Epub 2014 Apr 3.

Abstract

Adrenal Cushing's syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads 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), adrenocorticotropic hormone-independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing's syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / metabolism*
  • Adrenocortical Adenoma / genetics*
  • Adrenocortical Adenoma / metabolism*
  • Amino Acid Substitution
  • Arginine / genetics
  • Catalytic Domain / genetics
  • Cells, Cultured
  • Cushing Syndrome / genetics*
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / chemistry
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
  • Glucocorticoids / metabolism
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Hydrocortisone / metabolism*
  • Leucine / genetics
  • Methyltransferases / genetics
  • Microtubule-Associated Proteins / genetics
  • Mutation

Substances

  • CLASP2 protein, human
  • Glucocorticoids
  • Microtubule-Associated Proteins
  • Arginine
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human
  • Leucine
  • Hydrocortisone

Supplementary concepts

  • Acth-Independent Macronodular Adrenal Hyperplasia