Published Online April 3 2014
Science 23 May 2014:
Vol. 344 no. 6186 pp. 913-917
DOI: 10.1126/science.1249480
REPORT
Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome
Yanan Cao1,*, Minghui He2,*, Zhibo Gao2,*, Ying Peng1, Yanli Li1, Lin Li2, Weiwei Zhou1, Xiangchun Li2, Xu Zhong1, Yiming Lei2, Tingwei Su1, Hang Wang2, Yiran Jiang1, Lin Yang2, Wei Wei1, Xu Yang2, Xiuli Jiang1, Li Liu2, Juan He1, Junna Ye1, Qing Wei3, Yingrui Li2, Weiqing Wang1,†, Jun Wang2,4,5,6,7,†, Guang Ning1,8,†
+ Author Affiliations
1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
2BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
3Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
4Department of Biology, University of Copenhagen, Copenhagen, Denmark.
5King Abdulaziz University, Jeddah, Saudi Arabia.
6Macau University of Science and Technology, Macau, China.
7Department of Medicine, University of Hong Kong, Hong Kong.
8Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
↵†Corresponding author. E-mail: guangning@medmail.com.cn (G.N.); wangj@genomics.org.cn (J.W.); wqingw@hotmail.com (W.W.)
↵* These authors contributed equally to this work.
ABSTRACTEDITOR'S SUMMARY
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.
Received for publication 9 December 2013.
Accepted for publication 21 March 2014.