Age-Dependent Role of Armc5 in Mouse Adrenal: From Hypo- to Hyper Function

Presentation Number: MON 360
Date of Presentation: April 3rd, 2017

Annabel Sophie Berthon*1, Fabio R. Faucz2, Stéphanie Espiard3, Ludivine Drougat4, Jerome Yves Bertherat5 and Constantine A Stratakis6
1National Institutes of Health (NIH), Bethesda, MD, 2National Institute of Health, Bethesda, MD, 3Referral Center for Rare Adrenal Diseases, Paris, France, 4INSERM U 1016, CNRS 8104, Institut Cochin, Paris Descartes University, Paris, France, 5INSERM U 1016, Cochin Institute, Paris Descartes University, Paris, France, 6Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD


Mutations in Armadillo repeat containing 5 (ARMC5) gene have recently been discovered in Primary Macronodular Adrenal Hyperplasia (PMAH), a rare genetic cause of Cushing syndrome. These mutations inactivate ARMC5, first at the germline, and then at the somatic level, suggesting that ARMC5 may function as a tumor suppressor gene in the adrenal cortex. However, its function remains unclear. In order to better understand its role, we generated and characterized a mouse model for Armc5 deficiency. Surprisingly, most of Armc5 knockout (Armc5-/-) mice die during early embryonic development around 6.5 and 8.5 days. These embryos do not undergo proper gastrulation, as demonstrated by the absence of mesoderm development at E7.5 and they are eventually resorbed. Armc5 heterozygote mice (Armc5+/-) have normal embryonic development but at 1 year of age, they develop hypocorticosteronism associated with decreased of PKA activity in the adrenal glands. This is at least in part due to a decrease of catalytic subunit a of PKA expression both at RNA and protein level. However, this is a transient situation as shown by the elevation of corticosterone level and even hypercorticosteronism observed in a subset of our mice (N=4) at 14 months of age. This work is ongoing but, in conclusion, our preliminary data indicate that ARMC5 defects in mice provide a good analogy of what Armc5 defects cause in humans with PMAH. We also clearly show that ARMC5 is essential for early embryonic development; its role there remains to be determined.


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