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3. Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism

Author

Rege, Juilee, Bandulik, Sascha, Nanba, Kazutaka, Kosmann, Carla, Blinder, Amy R., Plain, Allein, Vats, Pankaj, Kumar-Sinha, Chandan, Lerario, Antonio M., Else, Tobias, Yamazaki, Yuto, Satoh, Fumitoshi, Sasano, Hironobu, Giordano, Thomas J., Williams, Tracy Ann, Reincke, Martin, Turcu, Adina F., Udager, Aaron M., Warth, Richard, and Rainey, William E.

Published
2023
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4. Circulating 11-oxygenated androgens across species

Author

Rege, Juilee, Garber, Scott, Conley, Alan J, Elsey, Ruth M, Turcu, Adina F, Auchus, Richard J, and Rainey, William E

Subjects
Biological Sciences, Genetics, Contraception/Reproduction, Androgens, Animals, Dehydroepiandrosterone, Dehydroepiandrosterone Sulfate, Female, Male, Species Specificity, Testosterone, Adrenal, Steroids, 11-Oxyandrogens, Primates, Analytical Chemistry, Biochemistry and Cell Biology, Endocrinology & Metabolism, Biochemistry and cell biology, Analytical chemistry
Abstract

The androgen precursors, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are produced in high amounts by the adrenal cortex primarily in humans and a few other primates. The human adrenal also secretes 11-oxygenated androgens (11-oxyandrogens), including 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), of which 11OHT and 11KT are bioactive androgens. The 11-oxyandrogens, particularly 11KT, have been recognized as biologically important testicular androgens in teleost fishes for decades, but their physiological contribution in humans has only recently been established. Beyond fish and humans, however, the presence of 11-oxyandrogens in other species has not been investigated. This study provides a comprehensive analysis of a set of C19 steroids, including the traditional androgens and 11-oxyandrogens, across 18 animal species. As previously shown, serum DHEA and DHEAS were much higher in primates than all other species. Circulating 11-oxyandrogens, especially 11KT, were observed in notable amounts in male, but not in female trout, consistent with gonadal origin in fish. The circulating concentrations of 11-oxyandrogens ranged from 0.1 to 10 nM in pigs, guinea pigs and in all the primates studied (rhesus macaque, baboon, chimpanzee and human) but not in rats or mice, and 11OHA4 was consistently the most abundant. In contrast to fish, serum 11KT concentrations were similar in male and female primates for each species, despite significantly higher circulating testosterone in males, suggesting that 11KT production in these species is not testis-dependent and primarily originates from adrenal-derived 11-oxyandrogen precursors.

Published
2019

9. Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation

Author

Taylor, Matthew J., Ullenbruch, Matthew R., Frucci, Emily C., Rege, Juilee, Ansorge, Mark S., Gomez-Sanchez, Celso E., Begum, Salma, Laufer, Edward, Breault, David T., and Rainey, William E.

Subjects
University of Michigan, Genetic engineering, Hyperaldosteronism, Cytochrome P-450, Hypertension, Angiotensin II, Aldosterone, Glucocorticoids, Therapeutics, Enzymes
Abstract

Introduction The adrenal glands synthesize and secrete steroid hormones that play critical roles in the regulation of electrolyte balance, blood pressure, carbohydrate metabolism, and responses to stress. To accomplish these [...], The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the reninangiotensin II (Angll) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by Angll activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal- wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.

Published
2020
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13. OR02-01 Somatic Mutations In The Zinc Transporter ZnT1 Cause Primary Aldosteronism

Author

Rege, Juilee, primary, Bandulik, Sascha, additional, Nanba, Kazutaka, additional, Kosmann, Carla, additional, Blinder, Amy, additional, Plain, Allen, additional, Vats, Pankaj, additional, Kumar-Sinha, Chandan, additional, Marcondes Lerario, Antonio, additional, Else, Tobias, additional, Yamazaki, Yuto, additional, Satoh, Fumitoshi, additional, Sasano, Hironobu, additional, Giordano, Thomas J, additional, Ann Williams, Tracy, additional, Reincke, Martin, additional, Turcu, Adina, additional, Udager, Aaron, additional, Warth, Richard, additional, and Rainey, William E, additional

Published
2023
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16. Supplementary Data from β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., primary, Finco, Isabella, primary, LaPensee, Christopher R., primary, Rege, Juilee, primary, Solon, April L., primary, Little, Donald W., primary, Else, Tobias, primary, Almeida, Madson Q., primary, Dang, Derek, primary, Haggerty-Skeans, James, primary, Apfelbaum, April A., primary, Vinco, Michelle, primary, Wakamatsu, Alda, primary, Mariani, Beatriz M.P., primary, Amorim, Larissa Costa, primary, Latronico, Ana Claudia, primary, Mendonca, Berenice B., primary, Zerbini, Maria Claudia N., primary, Lawlor, Elizabeth R., primary, Ohi, Ryoma, primary, Auchus, Richard J., primary, Rainey, William E., primary, Marie, Suely K.N., primary, Giordano, Thomas J., primary, Venneti, Sriram, primary, Fragoso, Maria Candida Barisson Villares, primary, Breault, David T., primary, Lerario, Antonio Marcondes, primary, and Hammer, Gary D., primary

Published
2023
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17. Data from β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., primary, Finco, Isabella, primary, LaPensee, Christopher R., primary, Rege, Juilee, primary, Solon, April L., primary, Little, Donald W., primary, Else, Tobias, primary, Almeida, Madson Q., primary, Dang, Derek, primary, Haggerty-Skeans, James, primary, Apfelbaum, April A., primary, Vinco, Michelle, primary, Wakamatsu, Alda, primary, Mariani, Beatriz M.P., primary, Amorim, Larissa Costa, primary, Latronico, Ana Claudia, primary, Mendonca, Berenice B., primary, Zerbini, Maria Claudia N., primary, Lawlor, Elizabeth R., primary, Ohi, Ryoma, primary, Auchus, Richard J., primary, Rainey, William E., primary, Marie, Suely K.N., primary, Giordano, Thomas J., primary, Venneti, Sriram, primary, Fragoso, Maria Candida Barisson Villares, primary, Breault, David T., primary, Lerario, Antonio Marcondes, primary, and Hammer, Gary D., primary

Published
2023
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18. Supplementary Information from β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., primary, Finco, Isabella, primary, LaPensee, Christopher R., primary, Rege, Juilee, primary, Solon, April L., primary, Little, Donald W., primary, Else, Tobias, primary, Almeida, Madson Q., primary, Dang, Derek, primary, Haggerty-Skeans, James, primary, Apfelbaum, April A., primary, Vinco, Michelle, primary, Wakamatsu, Alda, primary, Mariani, Beatriz M.P., primary, Amorim, Larissa Costa, primary, Latronico, Ana Claudia, primary, Mendonca, Berenice B., primary, Zerbini, Maria Claudia N., primary, Lawlor, Elizabeth R., primary, Ohi, Ryoma, primary, Auchus, Richard J., primary, Rainey, William E., primary, Marie, Suely K.N., primary, Giordano, Thomas J., primary, Venneti, Sriram, primary, Fragoso, Maria Candida Barisson Villares, primary, Breault, David T., primary, Lerario, Antonio Marcondes, primary, and Hammer, Gary D., primary

Published
2023
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20. β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., additional, Finco, Isabella, additional, LaPensee, Christopher R., additional, Rege, Juilee, additional, Solon, April L., additional, Little, Donald W., additional, Else, Tobias, additional, Almeida, Madson Q., additional, Dang, Derek, additional, Haggerty-Skeans, James, additional, Apfelbaum, April A., additional, Vinco, Michelle, additional, Wakamatsu, Alda, additional, Mariani, Beatriz M.P., additional, Amorim, Larissa Costa, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B., additional, Zerbini, Maria Claudia N., additional, Lawlor, Elizabeth R., additional, Ohi, Ryoma, additional, Auchus, Richard J., additional, Rainey, William E., additional, Marie, Suely K.N., additional, Giordano, Thomas J., additional, Venneti, Sriram, additional, Fragoso, Maria Candida Barisson Villares, additional, Breault, David T., additional, Lerario, Antonio Marcondes, additional, and Hammer, Gary D., additional

Published
2023
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21. Abstract 1501: Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., additional, Finco, Isabella, additional, LaPensee, Christopher R., additional, Rege, Juilee, additional, Little, Donald W., additional, Else, Tobias, additional, Almeida, Madson Q., additional, Dang, Derek, additional, Haggerty-Skeans, James, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B., additional, Auchus, Richard J., additional, Rainey, William E., additional, Marie, Suely K., additional, Giordano, Thomas J., additional, Venneti, Sriram, additional, Fragoso, Maria Candida B., additional, Breault, David T., additional, Lerario, Antonio M., additional, and Hammer, Gary D., additional

Published
2023
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22. Supplemental legend from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Mohan, Dipika R., primary, Lerario, Antonio Marcondes, primary, Else, Tobias, primary, Mukherjee, Bhramar, primary, Almeida, Madson Q., primary, Vinco, Michelle, primary, Rege, Juilee, primary, Mariani, Beatriz M. P., primary, Zerbini, Maria Claudia N., primary, Mendonca, Berenice B., primary, Latronico, Ana Claudia, primary, Marie, Suely K. N., primary, Rainey, William E., primary, Giordano, Thomas J., primary, Fragoso, Maria Candida B. V., primary, and Hammer, Gary D., primary

Published
2023
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23. Supplementary Figures S1-S7 from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Mohan, Dipika R., primary, Lerario, Antonio Marcondes, primary, Else, Tobias, primary, Mukherjee, Bhramar, primary, Almeida, Madson Q., primary, Vinco, Michelle, primary, Rege, Juilee, primary, Mariani, Beatriz M. P., primary, Zerbini, Maria Claudia N., primary, Mendonca, Berenice B., primary, Latronico, Ana Claudia, primary, Marie, Suely K. N., primary, Rainey, William E., primary, Giordano, Thomas J., primary, Fragoso, Maria Candida B. V., primary, and Hammer, Gary D., primary

Published
2023
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24. Supplementary Table S9 from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Mohan, Dipika R., primary, Lerario, Antonio Marcondes, primary, Else, Tobias, primary, Mukherjee, Bhramar, primary, Almeida, Madson Q., primary, Vinco, Michelle, primary, Rege, Juilee, primary, Mariani, Beatriz M. P., primary, Zerbini, Maria Claudia N., primary, Mendonca, Berenice B., primary, Latronico, Ana Claudia, primary, Marie, Suely K. N., primary, Rainey, William E., primary, Giordano, Thomas J., primary, Fragoso, Maria Candida B. V., primary, and Hammer, Gary D., primary

Published
2023
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25. Supplementary Tables S3, S4, S6, S7, S8 from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Mohan, Dipika R., primary, Lerario, Antonio Marcondes, primary, Else, Tobias, primary, Mukherjee, Bhramar, primary, Almeida, Madson Q., primary, Vinco, Michelle, primary, Rege, Juilee, primary, Mariani, Beatriz M. P., primary, Zerbini, Maria Claudia N., primary, Mendonca, Berenice B., primary, Latronico, Ana Claudia, primary, Marie, Suely K. N., primary, Rainey, William E., primary, Giordano, Thomas J., primary, Fragoso, Maria Candida B. V., primary, and Hammer, Gary D., primary

Published
2023
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27. Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis

Author

Ghayee, Hans K., primary, Xu, Yiling, additional, Hatch, Heather, additional, Brockway, Richard, additional, Multani, Asha S., additional, Gu, Tongjun, additional, Bollag, Wendy B., additional, Turcu, Adina, additional, Rainey, William E., additional, Rege, Juilee, additional, Nanba, Kazutaka, additional, Bhagwandin, Vikash J., additional, Nwariaku, Fiemu, additional, Stastny, Victor, additional, Gazdar, Adi F., additional, Shay, Jerry W., additional, Auchus, Richard J., additional, and Tevosian, Sergei G., additional

Published
2022
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29. RF21 | PSAT76 Epigenetic Programs Stabilize a Differentiated Cell State Required for Sustained Proliferation in Adrenocortical Carcinoma

Author

Mohan, Dipika, primary, Borges, Kleiton, additional, Finco, Isabella, additional, LaPensee, Christopher, additional, Rege, Juilee, additional, Little, Donald, additional, Else, Tobias, additional, Almeida, Madson, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice, additional, Auchus, Richard, additional, Rainey, William, additional, Marie, Suely, additional, Giordano, Thomas, additional, Venneti, Sriram, additional, Candida Fragoso, Maria, additional, Breault, David, additional, Lerario, Antonio, additional, and Hammer, Gary, additional

Published
2022
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33. β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

Author

Mohan, Dipika R, primary, Borges, Kleiton S, additional, Finco, Isabella, additional, LaPensee, Christopher R, additional, Rege, Juilee, additional, Solon, April L, additional, Little, Donald W, additional, Else, Tobias, additional, Almeida, Madson Q, additional, Dang, Derek, additional, Haggerty-Skeans, James, additional, Apfelbaum, April A, additional, Vinco, Michelle, additional, Wakamatsu, Alda, additional, Mariani, Beatriz M P, additional, Amorin, Larissa, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B, additional, Zerbini, Maria Claudia N, additional, Lawlor, Elizabeth R, additional, Ohi, Ryoma, additional, Auchus, Richard J, additional, Rainey, William E, additional, Marie, Suely K N, additional, Giordano, Thomas J, additional, Venneti, Sriram, additional, Fragoso, Maria Candida B V, additional, Breault, David T, additional, Lerario, Antonio Marcondes, additional, and Hammer, Gary D, additional

Published
2022
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34. Somatic SLC30A1mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism

Author

Rege, Juilee, Bandulik, Sascha, Nanba, Kazutaka, Kosmann, Carla, Blinder, Amy R., Plain, Allein, Vats, Pankaj, Kumar-Sinha, Chandan, Lerario, Antonio M., Else, Tobias, Yamazaki, Yuto, Satoh, Fumitoshi, Sasano, Hironobu, Giordano, Thomas J., Williams, Tracy Ann, Reincke, Martin, Turcu, Adina F., Udager, Aaron M., Warth, Richard, and Rainey, William E.

Abstract

Primary aldosteronism (PA) is the most common form of endocrine hypertension and is characterized by inappropriately elevated aldosterone production via a renin-independent mechanism. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1in four APAs and one APN (p.L51_A57del, n= 3; p.L49_L55del, n= 2). SLC30A1encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1variants are situated close to the zinc-binding site (His43 and Asp47) in transmembrane domain II and probably cause abnormal ion transport. Cases of PA with SLC30A1mutations showed male dominance and demonstrated increased aldosterone and 18-oxocortisol concentrations. Functional studies of the SLC30A151_57delvariant in a doxycycline-inducible adrenal cell system revealed pathological Na+influx. An aberrant Na+current led to depolarization of the resting membrane potential and, thus, to the opening of voltage-gated calcium (Ca2+) channels. This resulted in an increase in cytosolic Ca2+activity, which stimulated CYP11B2mRNA expression and aldosterone production. Collectively, these data implicate zinc transporter alterations as a dominant driver of aldosterone excess in PA.

Published
2023
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37. Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis.

Author

Ghayee, Hans K., Xu, Yiling, Hatch, Heather, Brockway, Richard, Multani, Asha S., Gu, Tongjun, Bollag, Wendy B., Turcu, Adina, Rainey, William E., Rege, Juilee, Nanba, Kazutaka, Bhagwandin, Vikash J., Nwariaku, Fiemu, Stastny, Victor, Gazdar, Adi F., Shay, Jerry W., Auchus, Richard J., and Tevosian, Sergei G.

Subjects
CELL lines, HISTONE deacetylase inhibitors, ADRENAL cortex, ADENOMA, TUMOR necrosis factors
Abstract

The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient's macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Targeted Mutational Analysis of Cortisol-Producing Adenomas

Author

Rege, Juilee, primary, Hoxie, Jessie, additional, Liu, Chia-Jen, additional, Cash, Morgan N, additional, Luther, James M, additional, Gellert, Lan, additional, Turcu, Adina F, additional, Else, Tobias, additional, Giordano, Thomas J, additional, Udager, Aaron M, additional, Rainey, William E, additional, and Nanba, Kazutaka, additional

Published
2021
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