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

被引：185

作者：

Cao, Yanan ^{[1
]}

He, Minghui ^{[2
]}

Gao, Zhibo ^{[2
]}

Peng, Ying ^{[1
]}

Li, Yanli ^{[1
]}

Li, Lin ^{[2
]}

Zhou, Weiwei ^{[1
]}

Li, Xiangchun ^{[2
]}

Zhong, Xu ^{[1
]}

Lei, Yiming ^{[2
]}

Su, Tingwei ^{[1
]}

Wang, Hang ^{[2
]}

Jiang, Yiran ^{[1
]}

Yang, Lin ^{[2
]}

Wei, Wei ^{[1
]}

Yang, Xu ^{[2
]}

Jiang, Xiuli ^{[1
]}

Liu, Li ^{[2
]}

He, Juan ^{[1
]}

Ye, Junna ^{[1
]}

Wei, Qing ^{[3
]}

Li, Yingrui ^{[2
]}

Wang, Weiqing ^{[1
]}

Wang, Jun ^{[2
,4
,5
,6
,7
]}

Ning, Guang ^{[1
,8
,9
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Clin Ctr Endocrine & Metab Dis, Shanghai Key Lab Endocrine Tumors,Rui Jin Hosp, Shanghai 200030, Peoples R China

[2] BGI Shenzhen, BGI Shanghai, Shenzhen, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, Dept Pathol, Rui Jin Hosp, Shanghai 200030, Peoples R China

[4] Univ Copenhagen, Dept Biol, Copenhagen, Denmark

[5] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia

[6] Macau Univ Sci & Technol, Macau, Peoples R China

[7] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China

[8] Chinese Acad Sci, Shanghai Inst Biol Sci SIBS, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai, Peoples R China

[9] Shanghai Jiao Tong Univ, Sch Med SJTUSM, Shanghai 200030, Peoples R China

来源：

SCIENCE | 2014年 / 344卷 / 6186期

关键词：

ACUTE REGULATORY PROTEIN; CRYSTAL-STRUCTURE; GENE; HYPERPLASIA; SUBUNIT; NETWORK; TUMORS;

D O I：

10.1126/science.1249480

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Adrenal Cushing's syndromeis 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.

引用

页码：913 / 917

页数：5

共 25 条

[1]

A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis [J].