Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.
Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.
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DOI：
10.1038/s41588-021-00906-y
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发表时间：
2021-09
期刊：
影响因子：
30.8
通讯作者：
Brown, Morris J.
中科院分区：
文献类型：
--
作者：
Zhou, Junhua;Azizan, Elena A. B.;Cabrera, Claudia P.;Fernandes-Rosa, Fabio L.;Boulkroun, Sheerazed;Argentesi, Giulia;Cottrell, Emily;Amar, Laurence;Wu, Xilin;O'Toole, Sam;Goodchild, Emily;Marker, Alison;Senanayake, Russell;Garg, Sumedha;Akerstrom, Tobias;Backman, Samuel;Jordan, Suzanne;Polubothu, Satyamaanasa;Berney, Daniel M.;Gluck, Anna;Lines, Kate E.;Thakker, Rajesh V.;Tuthill, Antoinette;Joyce, Caroline;Kaski, Juan Pablo;Karet Frankl, Fiona E.;Metherell, Lou A.;Teo, Ada E. D.;Gurnell, Mark;Parvanta, Laila;Drake, William M.;Wozniak, Eva;Klinzing, David;Kuan, Jyn Ling;Tiang, Zenia;Gomez Sanchez, Celso E.;Hellman, Per;Foo, Roger S. Y.;Mein, Charles A.;Kinsler, Veronica A.;Bjorklund, Peyman;Storr, Helen L.;Zennaro, Maria-Christina;Brown, Morris J.
大多数产生醛固酮的腺瘤(APA)都有离子通道或转运体的功能获得突变。然而，它们在正常肾上腺中产生醛固酮的细胞团中的频率表明APA需要辅助驱动突变。在这里，我们通过3/41个APA的全外显子测序鉴定了CTNNB1和GNA11中的功能增益突变。对已知的CTNNB1突变的APA进一步测序，共发现27例中的16例(59%)具有体细胞突变GNA11或GNAQ的p.Gln209His、p.Gln209Pro或p.Gln209Leu突变。在与双突变APAs相邻的增生性肾小球带中发现GNA11单独突变。在我们的英国/爱尔兰队列中，10名患者中有9名出现在青春期、怀孕或更年期。在双突变APAs中上调10倍以上的多个转录本中，有一种是LHCGR，它是黄体生成或妊娠激素(人绒毛膜促性腺激素)的受体。肾上腺皮质细胞的转基因显示GNA11和CTNNB1突变对双突变APAs的醛固酮分泌和上调基因表达的影响是相加的。在肾上腺皮质，GNA11/Q突变在临床上似乎是沉默的，没有CTNNB1的辅助驱动突变。
Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
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影响因子：
4.6
作者：
Åkerström T;Maharjan R;Sven Willenberg H;Cupisti K;Ip J;Moser A;Stålberg P;Robinson B;Alexander Iwen K;Dralle H;Walz MK;Lehnert H;Sidhu S;Gomez-Sanchez C;Hellman P;Björklund P
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通讯作者：
Bjorklund, Peyman
影响因子：
30.8
作者：
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通讯作者：
Brown, Morris J.
影响因子：
11.2
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