Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.
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.
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.
Yanan
Y
Cao
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Minghui
M
He
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Zhibo
Z
Gao
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.
Ying
Y
Peng
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.
Yanli
Y
Li
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Lin
L
Li
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.
Weiwei
W
Zhou
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Xiangchun
X
Li
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.
Xu
X
Zhong
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Yiming
Y
Lei
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.
Tingwei
T
Su
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Hang
H
Wang
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.
Yiran
Y
Jiang
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Lin
L
Yang
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.
Wei
W
Wei
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Xu
X
Yang
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.
Xiuli
X
Jiang
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Li
L
Liu
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.
Juan
J
He
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.
Junna
J
Ye
Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Qing
Q
Wei
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Yingrui
Y
Li
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. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com.
Weiqing
W
Wang
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China. Department of Biology, University of Copenhagen, Copenhagen, Denmark. King Abdulaziz University, Jeddah, Saudi Arabia. Macau University of Science and Technology, Macau, China. Department of Medicine, University of Hong Kong, Hong Kong. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com.
Jun
J
Wang
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. 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. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com.
Guang
G
Ning
D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000235:genetics*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000737:chemistry / Q000235:genetics*; D005938:Glucocorticoids / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007930:Leucine / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation
C497851:CLASP2 protein, human; D005938:Glucocorticoids; D008869:Microtubule-Associated Proteins; D001120:Arginine; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human; D007930:Leucine; D006854:Hydrocortisone