RGD Reference Report - Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. - Rat Genome Database

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Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.

Authors: Sato, Yusuke  Maekawa, Shigekatsu  Ishii, Ryohei  Sanada, Masashi  Morikawa, Teppei  Shiraishi, Yuichi  Yoshida, Kenichi  Nagata, Yasunobu  Sato-Otsubo, Aiko  Yoshizato, Tetsuichi  Suzuki, Hiromichi  Shiozawa, Yusuke  Kataoka, Keisuke  Kon, Ayana  Aoki, Kosuke  Chiba, Kenichi  Tanaka, Hiroko  Kume, Haruki  Miyano, Satoru  Fukayama, Masashi  Nureki, Osamu  Homma, Yukio  Ogawa, Seishi 
Citation: Sato Y, etal., Science. 2014 May 23;344(6186):917-20. doi: 10.1126/science.1252328.
RGD ID: 13515122
Pubmed: (View Article at PubMed) PMID:24855271
DOI: Full-text: DOI:10.1126/science.1252328

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.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Prkaca  (protein kinase cAMP-activated catalytic subunit alpha)

Genes (Mus musculus)
Prkaca  (protein kinase, cAMP dependent, catalytic, alpha)

Genes (Homo sapiens)
PRKACA  (protein kinase cAMP-activated catalytic subunit alpha)


Additional Information