Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause - Archive ouverte HAL Access content directly
Journal Articles Nature Genetics Year : 2021

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

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Junhua Zhou
Emily Cottrell
Sam O’toole
Samuel Backman
Kate Lines
Rajesh Thakker
Juan Pablo Kaski
Lou Metherell
Ada Teo
Per Hellman
  • Function : Author
Roger Foo
Helen Storr
Morris Brown

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 3/41 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.

Dates and versions

inserm-03870719 , version 1 (24-11-2022)

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Cite

Junhua Zhou, Elena Azizan, Claudia Cabrera, Fabio Fernandes-Rosa, Sheerazed Boulkroun, et al.. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Nature Genetics, 2021, 53 (9), pp.1360-1372. ⟨10.1038/s41588-021-00906-y⟩. ⟨inserm-03870719⟩
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