Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

被引：162

作者：

Sato, Yusuke ^{[1
,2
]}

Maekawa, Shigekatsu ^{[2
]}

Ishii, Ryohei ^{[3
]}

Sanada, Masashi ^{[1
]}

Morikawa, Teppei ^{[4
]}

Shiraishi, Yuichi ^{[5
]}

Yoshida, Kenichi ^{[1
]}

Nagata, Yasunobu ^{[1
]}

Sato-Otsubo, Aiko ^{[1
]}

Yoshizato, Tetsuichi ^{[1
]}

Suzuki, Hiromichi ^{[1
]}

Shiozawa, Yusuke ^{[1
]}

Kataoka, Keisuke ^{[1
]}

Kon, Ayana ^{[1
]}

Aoki, Kosuke ^{[1
]}

Chiba, Kenichi ^{[5
]}

Tanaka, Hiroko ^{[6
]}

Kume, Haruki ^{[2
]}

Miyano, Satoru ^{[5
,6
]}

Fukayama, Masashi ^{[4
]}

Nureki, Osamu ^{[3
]}

Homma, Yukio ^{[2
]}

Ogawa, Seishi ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[2] Univ Tokyo, Grad Sch Med, Dept Urol, Tokyo, Japan

[3] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 113, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Pathol, Tokyo, Japan

[5] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo, Japan

[6] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Sequence Anal, Tokyo, Japan

来源：

SCIENCE | 2014年 / 344卷 / 6186期

基金：

日本学术振兴会;

关键词：

PROTEIN-KINASE; ADRENAL-HYPERPLASIA; CATALYTIC SUBUNIT; RESPONSE-ELEMENT; PHOSPHODIESTERASE; BINDING; GENE; PDE11A;

D O I：

10.1126/science.1252328

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：917 / 920

页数：4

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