英国伦敦玛丽女王大学Morris J. Brown等研究人员合作揭示醛固酮腺瘤中的体细胞突变。相关论文于2021年8月12日在线发表在《自然—遗传学》杂志上。

通过对3/41个醛固酮腺瘤（APA）进行全外显子组测序，研究人员确定了CTNNB1和GNA11的功能获得突变。对已知的CTNNB1突变的APA进一步测序，研究人员发现27个APA中共有16个（59%）的GNA11或GNAQ发生了体细胞p.Gln209His、p.Gln209Pro或p.Gln209Leu突变。在邻近双突变APA的增生性肾小球带中发现有单发的GNA11突变。在英国/爱尔兰队列中，10名患者中有9名在青春期、怀孕或绝经期出现。

在双突变体APA中上调超过10倍的多个转录物中，有LHCGR，即黄体激素或妊娠激素（人绒毛膜促性腺激素）的受体。肾上腺皮质细胞的转染显示GNA11和CTNNB1突变对醛固酮的分泌和双突变APA中上调的基因的表达有附加影响。在肾上腺皮质中，如果没有CTNNB1的同源突变，GNA11/Q突变在临床上显得很沉默。

据悉，大多数APA有离子通道或转运器的功能增益体细胞突变。然而，它们在正常肾上腺产生醛固酮的细胞群中的频率表明，在APA中需要有子代突变。

附：英文原文

Title: Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Author: Zhou, Junhua, Azizan, Elena A. B., Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Argentesi, Giulia, Cottrell, Emily, Amar, Laurence, Wu, Xilin, OToole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, kerstrm, 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., Bjrklund, Peyman, Storr, Helen L., Zennaro, Maria-Christina, Brown, Morris J.

Issue&Volume: 2021-08-12

Abstract: 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 3/41APAs. 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.

DOI: 10.1038/s41588-021-00906-y

Source: https://www.nature.com/articles/s41588-021-00906-y