Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

Yusuke Sato, Shigekatsu Maekawa, Ryohei Ishii, Masashi Sanada, Teppei Morikawa, Yuichi Shiraishi, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Tetsuichi Yoshizato, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Ayana Kon, Kosuke Aoki, Kenichi Chiba, Hiroko Tanaka, Haruki Kume, Satoru Miyano, Masashi FukayamaOsamu Nureki, Yukio Homma, Seishi Ogawa

Research output: Contribution to journalArticlepeer-review

158 Citations (Scopus)


Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome.The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.

Original languageEnglish
Pages (from-to)917-920
Number of pages4
Issue number6186
Publication statusPublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • General


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