title: Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.
abstract: 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.
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigekatsu
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Ayana
authors.initials: A
authors.lastname: Kon
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. sogawa-tky@umin.ac.jp homma-uro@umin.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. sogawa-tky@umin.ac.jp homma-uro@umin.ac.jp.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018246:Adrenocortical Adenoma / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D051381:Rats
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D000324:Adrenocorticotropic Hormone; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human