Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause
| العنوان: | Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause |
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| المؤلفون: | Sam O’Toole, Peyman Björklund, Samuel Backman, Per Hellman, Eva Wozniak, Sumedha Garg, Morris J. Brown, Emily Goodchild, Junhua Zhou, Alison Marker, Antoinette Tuthill, Giulia Argentesi, Caroline Joyce, Xilin Wu, Sheerazed Boulkroun, Celso E Gomez Sanchez, Russell Senanayake, Satyamaanasa Polubothu, Kate E Lines, Lou Metherell, Suzanne Jordan, Jyn Ling Kuan, Zenia Tiang, Laila Parvanta, Fiona E. Karet Frankl, Veronica A Kinsler, Rajesh V. Thakker, Elena A.B. Azizan, Fabio L. Fernandes-Rosa, Maria-Christina Zennaro, David Klinzing, Laurence Amar, Emily Cottrell, William Drake, Helen L Storr, Ada E. D. Teo, Juan Pablo Kaski, Roger Foo, Charles A. Mein, Tobias Åkerström, Daniel M. Berney, Claudia P. Cabrera, Anna K Gluck, Mark Gurnell |
| المساهمون: | Queen Mary University of London (QMUL), National University of Malaysia [Bandar Baru Bangi] (UKM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Addenbrooke's Hospital, Cambridge University NHS Trust, Metabolic Research Laboratories [Cambridge, UK] (University of Cambridge), Wellcome Trust - MRC Cambridge-Addenbrooke’s Hospital [Cambridge, UK], Uppsala University, Royal Free Hospital [London, UK], University College of London [London] (UCL), University of Oxford, Cork University Hospital [Cork, Ireland] (CUH), University of Cambridge [UK] (CAM), National University of Singapore (NUS), St Bartholomew's Hospital (London), Agency for science, technology and research [Singapore] (A*STAR), University of Mississippi Medical Center (UMMC), Fernandes Rosa, Fabio |
| المصدر: | Nat Genet Nature Genetics Nature Genetics, 2021, 53 (9), pp.1360-1372. ⟨10.1038/s41588-021-00906-y⟩ |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, endocrine system, medicine.medical_specialty, Adolescent, education, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Article, Human chorionic gonadotropin, chemistry.chemical_compound, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pregnancy, Internal medicine, Hyperaldosteronism, Genetics, medicine, Humans, Aldosterone, beta Catenin, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, GNA11, Adrenal gland, Adrenal cortex, Puberty, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, Adrenal Cortex Neoplasms, GTP-Binding Protein alpha Subunits, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, Endocrinology, chemistry, Zona glomerulosa, Adrenocortical Adenoma, GTP-Binding Protein alpha Subunits, Gq-G11, Female, Menopause, GNAQ |
| الوصف: | 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. Sequence analysis identifies gain-of-function somatic mutations in GNA11 or GNAQ in CTNNB1-mutant aldosterone-producing adenomas. Most patients with these mutations presented during puberty, pregnancy or menopause, with elevated LHCGR expression. |
| تدمد: | 1546-1718 1061-4036 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f4b06af371bc122514ed8222140e35aTest https://doi.org/10.1038/s41588-021-00906-yTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0f4b06af371bc122514ed8222140e35a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15461718 10614036 |
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