Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

Yusuke Sato; Shigekatsu Maekawa; Ryohei Ishii; Masashi Sanada; Teppei Morikawa; Yuichi Shiraishi; Kenichi Yoshida; Yasunobu Nagata; Aiko Sato-Otsubo; Tetsuichi Yoshizato; Hiromichi Suzuki; Yusuke Shiozawa; Keisuke Kataoka; Ayana Kon; Kosuke Aoki; Kenichi Chiba; Hiroko Tanaka; Haruki Kume; Satoru Miyano; Masashi Fukayama; Osamu Nureki; Yukio Homma; Seishi Ogawa

doi:10.1126/science.1252328

Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

Yusuke Sato, Shigekatsu Maekawa, Ryohei Ishii, Masashi Sanada, Teppei Morikawa, Yuichi Shiraishi, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Tetsuichi Yoshizato, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Ayana Kon, Kosuke Aoki, Kenichi Chiba, Hiroko Tanaka, Haruki Kume, Satoru Miyano, Masashi FukayamaOsamu Nureki, Yukio Homma, Seishi Ogawa

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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.

Original language	English
Pages (from-to)	917-920
Number of pages	4
Journal	Science
Volume	344
Issue number	6186
DOIs	https://doi.org/10.1126/science.1252328
Publication status	Published - 2014
Externally published	Yes

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Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., Kataoka, K., Kon, A., Aoki, K., Chiba, K., Tanaka, H., Kume, H., Miyano, S., ... Ogawa, S. (2014). Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. Science, 344(6186), 917-920. https://doi.org/10.1126/science.1252328

Sato, Y, Maekawa, S, Ishii, R, Sanada, M, Morikawa, T, Shiraishi, Y, Yoshida, K, Nagata, Y, Sato-Otsubo, A, Yoshizato, T, Suzuki, H, Shiozawa, Y, Kataoka, K, Kon, A, Aoki, K, Chiba, K, Tanaka, H, Kume, H, Miyano, S, Fukayama, M, Nureki, O, Homma, Y & Ogawa, S 2014, 'Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome', Science, vol. 344, no. 6186, pp. 917-920. https://doi.org/10.1126/science.1252328

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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.",

author = "Yusuke Sato and Shigekatsu Maekawa and Ryohei Ishii and Masashi Sanada and Teppei Morikawa and Yuichi Shiraishi and Kenichi Yoshida and Yasunobu Nagata and Aiko Sato-Otsubo and Tetsuichi Yoshizato and Hiromichi Suzuki and Yusuke Shiozawa and Keisuke Kataoka and Ayana Kon and Kosuke Aoki and Kenichi Chiba and Hiroko Tanaka and Haruki Kume and Satoru Miyano and Masashi Fukayama and Osamu Nureki and Yukio Homma and Seishi Ogawa",

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doi = "10.1126/science.1252328",

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AU - Sato, Yusuke

AU - Maekawa, Shigekatsu

AU - Ishii, Ryohei

AU - Sanada, Masashi

AU - Morikawa, Teppei

AU - Shiraishi, Yuichi

AU - Yoshida, Kenichi

AU - Nagata, Yasunobu

AU - Sato-Otsubo, Aiko

AU - Yoshizato, Tetsuichi

AU - Suzuki, Hiromichi

AU - Shiozawa, Yusuke

AU - Kataoka, Keisuke

AU - Kon, Ayana

AU - Aoki, Kosuke

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Kume, Haruki

AU - Miyano, Satoru

AU - Fukayama, Masashi

AU - Nureki, Osamu

AU - Homma, Yukio

AU - Ogawa, Seishi

PY - 2014

Y1 - 2014

N2 - 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.

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Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

Abstract

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