Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome-Reference-Cited by-同舟云学术

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

Published:2014-05-23 Issue:6186 Volume:344 Page:913-917
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Cao Yanan¹,He Minghui²,Gao Zhibo²,Peng Ying¹,Li Yanli¹,Li Lin²,Zhou Weiwei¹,Li Xiangchun²,Zhong Xu¹,Lei Yiming²,Su Tingwei¹,Wang Hang²,Jiang Yiran¹,Yang Lin²,Wei Wei¹,Yang Xu²,Jiang Xiuli¹,Liu Li²,He Juan¹,Ye Junna¹,Wei Qing³,Li Yingrui²,Wang Weiqing¹,Wang Jun²⁴⁵⁶⁷,Ning Guang¹⁸

Affiliation:

1. Shanghai 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.

2. BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.

3. Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

4. Department of Biology, University of Copenhagen, Copenhagen, Denmark.

5. King Abdulaziz University, Jeddah, Saudi Arabia.

6. Macau University of Science and Technology, Macau, China.

7. Department of Medicine, University of Hong Kong, Hong Kong.

8. Laboratory 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.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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