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1. Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Author

Wu, Xilin, Azizan, Elena A. B., Goodchild, Emily, Garg, Sumedha, Hagiyama, Man, Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Kuan, Jyn Ling, Tiang, Zenia, David, Alessia, Murakami, Masanori, Mein, Charles A., Wozniak, Eva, Zhao, Wanfeng, Marker, Alison, Buss, Folma, Saleeb, Rebecca S., Salsbury, Jackie, Tezuka, Yuta, Satoh, Fumitoshi, Oki, Kenji, Udager, Aaron M., Cohen, Debbie L., Wachtel, Heather, King, Peter J., Drake, William M., Gurnell, Mark, Ceral, Jiri, Ryska, Ales, Mustangin, Muaatamarulain, Wong, Yin Ping, Tan, Geok Chin, Solar, Miroslav, Reincke, Martin, Rainey, William E., Foo, Roger S., Takaoka, Yutaka, Murray, Sandra A., Zennaro, Maria-Christina, Beuschlein, Felix, Ito, Akihiko, and Brown, Morris J.

Published
2023
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2. Role of two genes, CACNA1D and CADM1, with common or rare mutations in aldosterone producing adenomas of the adrenal

Author

Garg, Sumedha and Gurnell, Mark

Subjects
616.99, aldosterone, adenoma, somatic mutations, hypertension
Abstract

Primary aldosteronism (PA) accounts for 5-10% of all hypertension. One of the major causes of PA is sporadic formation of aldosterone-producing adenomas (APAs). These benign tumours develop in the cortical region of adrenal glands and autonomously secrete excessive amounts of aldosterone. This hormone increases sodium retention and water reabsorption by the kidneys, leading to high blood pressure. Landmark discoveries of somatic mutations in APAs led to better understanding of molecular mechanisms causing autonomous aldosterone secretion. The first mutations were found in KCNJ5, followed by ATP1A1, ATP2B3 and CACNA1D, all encoding cation-channels or transporters. Several in vitro studies showed disruption of cellular ion-balance leading to the phenotype of hyper-aldosterone secretion from APAs. Following our lab's discovery of initial four somatic mutations by whole exome sequencing, over 30 single-base change mutations have been reported in the CACNA1D gene, which encodes the a1 subunit of an L-type Ca2+ channel (LTCC), CaV1.3. Initial and several subsequent mutations cause electrophysiological gain-of-function with increased activation and/or slowed inactivation of CaV1.3. Prior to the discovery of these mutations, L-type Ca2+ channels were not considered important in regulation of aldosterone production. In the first part of my thesis, I investigated two of the mutations and showed that the gain-of-function results in increased aldosterone secretion from an adrenocortical carcinoma cell line, H295R, when transiently transfected with the mutants. I also showed that CaV1.3 can play a role in physiological aldosterone secretion, finding that CYP11B2 expression is reduced by 50% in the adrenals of CaV1.3 knockout mice. The discovery of mutations in CACNA1D led to a drug discovery challenge award from a pharmaceutical company in which high-throughput screening of CaV1.3-expressing cells was undertaken against the company's 1.8M compound library. I identified the adrenal isoforms of the channel's alpha and beta subunits (CACNA1D and CACNB2), and helped development of the stable HEK293 cell line used for screening. This led to 3 tool compounds (A, B & C) that were selective antagonists for CaV1.3 over another family member of the ion channels in high-throughput electrophysiological experiments using IonWorks Barracuda and QPatch platforms. I showed compound B to effectively inhibit aldosterone secretion in both H295R and primary adrenal cells isolated from a normal adrenal. This finding is a significant step in developing compound B further into a CaV1.3-selective drug for treating PA patients without cardiovascular side effects as in the case of existing dihydropyridine class of Ca2+ channel blockers. The second part of my thesis focused on genotyping and whole exome sequencing of 59 APAs from 52 patients, in order to identify further genes underlying primary aldosteronism. Mutations in previously reported genes were identified in 34 of the APAs (57.6%). CACNA1D was the most commonly mutated gene (20.3%) in this cohort, but not KCNJ5 (16.9%) as previously reported. This variation in the frequencies observed is perhaps due to the different methods used for screening PA. For example, many of our patients were detected by renin measurement in resistant hypertension, and their APA identified by a unique PET-CT (using C11 metomidate), in place of adrenal vein sampling. In addition to this, novel somatic mutation was found in a gene not encoding an ion channel, however, this protein was previously linked to cell-cell adhesion and tumour suppression. The gene identified is CADM1, a cell adhesion molecule 1, and the mutation found leads to substitution of uncharged by negatively charged amino acid in the single transmembrane domain of this cell surface protein. The likely significance of this discovery was greatly enhanced when we ascertained that one of the 'private' somatic mutations found on whole exome sequencing of APAs in Munich was in fact a similar substitution in the adjacent amino acid of the membrane-spanning domain. High expression of CADM1 in zona glomerulosa (ZG) was found, the site of aldosterone synthesis in the adrenal cortex and in the APAs, as well as the aldosterone producing cell clusters (APCCs) within the ZG. In vitro experiments using H295R cells showed both mutations in CADM1 lead to 10-20 fold upregulation of CYP11B2 transcription, on qPCR, resulting in 2-4-fold increase of aldosterone secretion, compared to the wild-type CADM1. Despite the introduction of a negative charge into the transmembrane domain, both mutants could translocate to the cell surface. The evidence to date, points to the loss of cell-cell adhesion in the presence of mutant CADM1 as the cause of uncontrolled aldosterone synthesis. Silencing of CADM1 in H295R cells revealed downregulation of aldosterone synthesis and secretion. Transcriptome analysis by RNAseq, of H295R cells expressing wild-type or mutant CADM1 or silenced CADM1 showed a large number of differentially expressed genes. Mutant CADM1 upregulated genes involved in steroidogenesis and ACTH response pathways. A possible role of CADM1 was found to be in the regulation of inter-cell communication via gap junction protein, connexin-43 (Cx43). This was upregulated with higher expression on plasma membrane in the CADM1 silenced cells. TSG101, a protein involved in lysosomal degradation of Cx43 was downregulated in the absence of CADM1 and possibly the mechanism for increased Cx43 expression. Also, immunostaining of adrenal sections showed internalised para-nuclear staining localisation of Cx43 in the ZG, APAs and APCCs, regions with high CADM1 expression compared to membranous localisation of Cx43 in ZF. In contrast to the common and numerous mutations in CACNA1D, mutations in CADM1 are rare. Nonetheless, they may enhance our understanding of the functional significance of glomerular structure of the outer zone of adrenal cortex, where cell-cell adhesion and intercellular communication appear critical for the regulation of aldosterone secretion.

Published
2019
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4. 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, O’Toole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, Åkerström, 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., Björklund, Peyman, Storr, Helen L., Zennaro, Maria-Christina, and Brown, Morris J.

Published
2021
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7. Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity

Author

Asai, Masato, Ramachandrappa, Shwetha, Joachim, Maria, Shen, Yuan, Zhang, Rong, Nuthalapati, Nikhil, Ramanathan, Visali, Strochlic, David E., Ferket, Peter, Linhart, Kirsten, Ho, Caroline, Novoselova, Tatiana V., Garg, Sumedha, Ridderstråle, Martin, Marcus, Claude, Hirschhorn, Joel N., Keogh, Julia M., O'Rahilly, Stephen, Chan, Li F., Clark, Adrian J., Farooqi, I. Sadaf, and Majzoub, Joseph A.

Published
2013

8. Market potential and value‐added opportunities of cold‐hardy berries and small fruits in the Intermountain West, USA.

Author

Garg, Sumedha, Leisso, Rachel, Kim, Sun‐Hwa, Mayhew, Emily, Song, Mei, Jarrett, Bridgid, and Kuo, Wan‐Yuan

Subjects
*SOUR cherry, *MARKET potential, *BERRIES, *VALUE added (Marketing), *FRUIT, *FARMERS
Abstract

Novel cold‐hardy berries and small fruits represent an opportunity for growers in the Intermountain West, USA, as the harsh environment is not suited for other common berries and small fruits. This study analyzed the fresh market and value‐added potential of haskap berries (Lonicera caerulea), saskatoon berries (Amelenchier alnifolia), and dwarf sour cherry (DSC) fruit (Prunus x kerrasis) by instrumental and consumer studies. Fresh and 2‐week stored haskap (cv. Aurora), saskatoon (Lee 3), and DSC (Romeo) were measured for fruit weight, flesh firmness, bulk titratable acidity, pH, and soluble solid content. Participants (n = 115) in at‐home sensory tests scored these fruits for overall liking (OL, 9‐point hedonic scale), purchase intent (PI, 5‐point scale), and willingness‐to‐pay (WTP, 5‐point scale). Ten participants further shared insight on these fruits in focus groups. Instrumental testing found a significant decrease in flesh firmness for 2‐week stored haskap, but the consumers' OL was still comparable to fresh haskap. The fresh and 2‐week stored haskap received significantly higher OL, PI, and WTP scores (7.7 ± 1.0, 3.8 ± 1.0, and $3.7 ± 1.0; 7.7 ± 1.2, 3.8 ± 1.1, and $3.7 ± 1.0, respectively) compared to saskatoon (6.1 ± 1.8, 2.8 ± 1.1, and $3.0 ± 0.9, respectively) and DSC (5.6 ± 2.2, 2.5 ± 1.2, and $3.1 ± 1.0, respectively) (α = 0.05). The focus groups indicated that participants want to support local produce. The participants expressed interest in fresh unprocessed haskap berries, but preferred saskatoon and DSC in different value‐added formats. Hence, this study concluded that there is an untapped fresh‐market potential for haskap berries and there are value‐added opportunities to extend the sale season and improve the palatability of saskatoon and DSC. Practical Application: This research has examined consumer perception of three species of novel small fruits by determining fresh‐market potential and linking this to the opportunity for value‐added product development. For haskap berries, the study not only indicated fresh market potential, but for the cultivar Aurora, consumer liking was not meaningfully altered by 2 weeks of cold storage. These results are meaningful because they will assist growers in the Intermountain West with market planning, including the possibility of formulating products that utilize these novel crops. This study provides growers the opportunity to diversify their income stream by utilizing local produce. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Author

Argentesi, Giulia, primary, Azizan, Elena, additional, Zhou, Junhua, additional, Cabrera, Claudia, additional, O’Toole, Sam, additional, Wu, Xilin, additional, Goodchild, Emily, additional, Cottrell, Emily, additional, Marker, Alison, additional, Senanayake, Russell, additional, Garg, Sumedha, additional, Jordan, Suzanne, additional, Berney, Dan, additional, Gluck, Anna, additional, Lines, Kate, additional, Thakker, Rajesh V, additional, Tuthill, Antoinette, additional, Joyce, Caroline, additional, Karet, Frankl Fiona, additional, Metherell, Lou, additional, Teo, Ada, additional, Gurnell, Mark, additional, Parvanta, Laila, additional, Drake, William, additional, Wozniak, Eva, additional, Mein, Chaz, additional, Kinsler, Veronika, additional, Storr, Helen, additional, and Brown, Morris, additional

Published
2021
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12. Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Author

Ramachandrappa, Shwetha, Raimondo, Anne, Cali, Anna M.G., Keogh, Julia M., Henning, Elana, Saeed, Sadia, Thompson, Amanda, Garg, Sumedha, Bochukova, Elena G., Brage, Soren, Trowse, Victoria, Wheeler, Eleanor, Sullivan, Adrienne E., Dattani, Mehul, Clayton, Peter E., Datta, Vippan, Bruning, John B., Wareham, Nick J., O'Rahilly, Stephen, Peet, Daniel J., Barroso, Ines, Whitelaw, Murray L., and Farooqi, I. Sadaf

Subjects
Obesity -- Genetic aspects, Genetic research, Genetic transcription -- Research, Hypothalamus -- Genetic aspects -- Physiological aspects, Health care industry
Abstract

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice [...]

Published
2013
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15. Somatic mutations of CADM1in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Author

Wu, Xilin, Azizan, Elena A. B., Goodchild, Emily, Garg, Sumedha, Hagiyama, Man, Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Kuan, Jyn Ling, Tiang, Zenia, David, Alessia, Murakami, Masanori, Mein, Charles A., Wozniak, Eva, Zhao, Wanfeng, Marker, Alison, Buss, Folma, Saleeb, Rebecca S., Salsbury, Jackie, Tezuka, Yuta, Satoh, Fumitoshi, Oki, Kenji, Udager, Aaron M., Cohen, Debbie L., Wachtel, Heather, King, Peter J., Drake, William M., Gurnell, Mark, Ceral, Jiri, Ryska, Ales, Mustangin, Muaatamarulain, Wong, Yin Ping, Tan, Geok Chin, Solar, Miroslav, Reincke, Martin, Rainey, William E., Foo, Roger S., Takaoka, Yutaka, Murray, Sandra A., Zennaro, Maria-Christina, Beuschlein, Felix, Ito, Akihiko, and Brown, Morris J.

Abstract

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n= 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2(aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2similarly to CADM1mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

Published
2023
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16. Somatic Mutations of GNA11 and GNAQ in CTNNB1-Mutant Aldosterone-Producing Adenomas Increases Aldosterone and Aldosterone Synthase (CYP11B2)

Author

Azizan, Elena A B, primary, Zhou, Junhua, additional, Cabrera, Claudia P, additional, Fernandes-Rosa, Fabio Luiz, additional, Boulkroun, Sheerazed, additional, Argentesi, Giulia, additional, Cottrell, Emily, additional, Amar, Laurence, additional, Wu, Xilin, additional, Marker, Alison, additional, Garg, Sumedha, additional, Akerstrom, Tobias, additional, Backman, Samuel, additional, Jordan, Suzanne, additional, Gluck, Anna Katharina, additional, Lines, Kate E, additional, Thakker, Rajesh V, additional, Tuthill, Antoinette A, additional, Joyce, Caroline Martha, additional, Metherell, Louise, additional, Teo, Ada, additional, Gurnell, Mark, additional, Parvanta, Laila, additional, Drake, William, additional, Wozniak, Eva, additional, Kuan, Jyn L, additional, Tiang, Zenia, additional, Hellman, Per, additional, Foo, Roger, additional, Mein, Chaz, additional, Kinsler, Veronica, additional, Bjorklund, Peyman, additional, Storr, Helen Louise, additional, Zennaro, Maria-Christina, additional, and Brown, Morris Jonathan, additional

Published
2021
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18. OR34-02 Somatic Transmembrane Domain Mutations of a Cell Adhesion Molecule, CADM1, Cause Primary Aldosteronism by Preventing Gap Junction Communication Between Adrenocortical Cells

Author

Wu, Xilin, primary, Garg, Sumedha, primary, Cabrera, Claudia P, primary, Azizan, Elena, primary, Zhou, Junhua, primary, Mein, Chaz, primary, Wozniak, Eva, primary, Zhao, Wanfeng, primary, Marker, Alison, primary, Buss, Folma, primary, Murakami, Masanori, primary, Reincke, Martin, primary, Takaoka, Yutaka, primary, Beuschlein, Felix, primary, Akihiko, Ito, primary, and Brown, Morris Jonathan, primary

Published
2020
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19. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaã«lle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Kã¶rner, Antje, Muddyman, Dawn, Mccarthy, Shane, Hinney, Anke, Hebebrand, Johanne, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M., Butterworth, Adam S., Danesh, John, Nordestgaard, Bã¸rge G, Nielsen, Sune F, Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inãª, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nichola, Jã¤ckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjã¸nneland, Anne, Clavel chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sã¡nchez, Marã­a josã©, Navarro, Carmen, Moreno iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Turki, Saeed Al, Anderson, Carl A., Anney, Richard, Antony, Dinu, Soler Artigas, Marã­a, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Dougla, Bobrow, Martin, Bolton, Patrick F., Boustred, Chri, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A., Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N. M., Day williams, Aaron, Dominiczak, Anna, Down, Thoma, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., Fitzpatrick, David R., Flicek, Paul, Floyd, Jame, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthia, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chri, Karczewski, Konrad J., Kaye, Jane, Keane, Thoma, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lã¶nnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Macarthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M., Moayyeri, Alireza, Morris, Andrew, Morris, Jame, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandro, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnstrã¶m, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petro, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D., Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou feng

Subjects
Multidisciplinary, Journal Article, General
Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as describedw previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017

20. Somatic transmembrane domain mutations of a cell adhesion molecule, CADM1, cause primary aldosteronism by preventing gap junction communication between adrenocortical cells

Author

Wu, Xilin, primary, Garg, Sumedha, additional, Cabrera, Claudia, additional, Azizan, Elena, additional, Zhou, Junhua, additional, Mein, Chaz, additional, Takaoka, Yutaka, additional, Wozniak, Eva, additional, Zhao, Wanfeng, additional, Marker, Alison, additional, Buss, Folma, additional, Murakami, Masanori, additional, Beuschlein, Felix, additional, Reincke, Martin, additional, Ito, Akihiko, additional, and Brown, Morris, additional

Published
2019
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21. Somatic mutations of GNA11and GNAQin 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, O’Toole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, Åkerström, 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., Björklund, Peyman, Storr, Helen L., Zennaro, Maria-Christina, and Brown, Morris J.

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 CTNNB1and GNA11by 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 GNA11or GNAQ. Solitary GNA11mutations 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 GNA11and CTNNB1mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Qmutations appear clinically silent without a codriver mutation of CTNNB1.

Published
2021
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24. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou Feng

Published
2017

27. Pregnancy, Primary Aldosteronism and Somatic CTNNB1 Mutations in the Adrenal

Author

Teo, Ada, Garg, Sumedha, Shaikh, Lalarukh Haris, Zhou, Junhua, Karet, Fiona, Gurnell, Mark, Happerfield, Lisa, Marker, Alison, Bienz, Mariann, Azizan, Elena AB, Brown, Morris J, Teo, Ada [0000-0002-8832-0409], Karet, Fiona [0000-0002-2457-2869], Gurnell, Mark [0000-0001-5745-6832], and Apollo - University of Cambridge Repository

Abstract

Recent discoveries of somatic mutations permit the recognition of sub-types of aldosterone-producing adenomas (APA) with different clinical presentations and pathology. Here we describe two women who presented in pregnancy, and one woman who presented post-menopause, with hyperaldosteronism. Their APAs harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed >100-fold higher levels of LHCGR and GNRHR, encoding gonadal receptors, than other APAs. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate towards their common gonad-adrenal precursor cell-type.

Published
2015

28. Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1

Author

Pearce, Laura R, Joe, Ray, Doche, Michael E, Su, Hsiao-Wen, Keogh, Julia M, Henning, Elana, Argetsinger, Lawrence S, Bochukova, Elena G, Cline, Joel M, Garg, Sumedha, Saeed, Sadia, Shoelson, Steven, O'Rahilly, Stephen, Barroso, Inês, Rui, Liangyou, Farooqi, I Sadaf, Carter-Su, Christin, Keogh, Julia [0000-0002-0399-4114], Henning, Elana [0000-0002-0399-4114], O'Rahilly, Stephen [0000-0003-2199-4449], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Adult, Leptin, Male, Adolescent, Mutation, Missense, Alternative Splicing, Young Adult, Humans, Insulin, Protein Isoforms, Female, Obesity, Child, Adaptor Proteins, Signal Transducing, Signal Transduction
Abstract

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

Published
2014

29. Regulation of aldosterone secretion by Cav1.3

Author

Xie, Catherine B., primary, Haris Shaikh, Lalarukh, additional, Garg, Sumedha, additional, Tanriver, Gizem, additional, Teo, Ada E. D., additional, Zhou, Junhua, additional, Maniero, Carmela, additional, Zhao, Wanfeng, additional, Kang, Soosung, additional, Silverman, Richard B., additional, Azizan, Elena A. B., additional, and Brown, Morris J., additional

Published
2016
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30. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation

Author

Pearce, Laura R, Atanassova, Neli, Banton, Matthew C, Bottomley, Bill, van der Klaauw, Agatha A, Revelli, Jean-Pierre, Hendricks, Audrey, Keogh, Julia M, Henning, Elana, Doree, Deon, Jeter-Jones, Sabrina, Garg, Sumedha, Bochukova, Elena G, Bounds, Rebecca, Ashford, Sofie, Gayton, Emma, Hindmarsh, Peter C, Shield, Julian PH, Crowne, Elizabeth, Barford, David, Wareham, Nick J, UK10K consortium, O'Rahilly, Stephen, Murphy, Michael P, Powell, David R, Barroso, Ines, Farooqi, I Sadaf, Keogh, Julia [0000-0002-0399-4114], Henning, Elana [0000-0002-0399-4114], Wareham, Nicholas [0000-0003-1422-2993], O'Rahilly, Stephen [0000-0003-2199-4449], Murphy, Mike [0000-0003-1115-9618], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Male, Models, Molecular, Proto-Oncogene Proteins B-raf, MAP Kinase Signaling System, Fatty Acids, Molecular Sequence Data, Age Factors, Hyperphagia, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Mice, Glucose, Animals, Humans, Female, Amino Acid Sequence, Obesity, Age of Onset, Insulin Resistance, Child, Energy Metabolism, Oxidation-Reduction, Sequence Alignment
Abstract

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Published
2013

31. Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin).

Author

Ee Der Teo, Ada, Garg, Sumedha, Johnson, Timothy Isaac, Wanfeng Zhao, Junhua Zhou, Gomez-Sanchez, Celso Enrique, Gurnell, Mark, Brown, Morris Jonathan, Teo, Ada Ee Der, Zhao, Wanfeng, and Zhou, Junhua

Abstract

Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which NPNT (nephronectin) was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function CTNNB1 mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and NPNT overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of NPNT in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2017
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32. A Homozygous Mutation in theTUBGene Associated with Retinal Dystrophy and Obesity

Author

Borman, Arundhati Dev, primary, Pearce, Laura R., additional, Mackay, Donna S., additional, Nagel‐Wolfrum, Kerstin, additional, Davidson, Alice E., additional, Henderson, Robert, additional, Garg, Sumedha, additional, Waseem, Naushin H., additional, Webster, Andrew R., additional, Plagnol, Vincent, additional, Wolfrum, Uwe, additional, Farooqi, I. Sadaf, additional, and Moore, Anthony T., additional

Published
2013
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33. KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

Author

Pearce, Laura R., primary, Atanassova, Neli, additional, Banton, Matthew C., additional, Bottomley, Bill, additional, van der Klaauw, Agatha A., additional, Revelli, Jean-Pierre, additional, Hendricks, Audrey, additional, Keogh, Julia M., additional, Henning, Elana, additional, Doree, Deon, additional, Jeter-Jones, Sabrina, additional, Garg, Sumedha, additional, Bochukova, Elena G., additional, Bounds, Rebecca, additional, Ashford, Sofie, additional, Gayton, Emma, additional, Hindmarsh, Peter C., additional, Shield, Julian P.H., additional, Crowne, Elizabeth, additional, Barford, David, additional, Wareham, Nick J., additional, O’Rahilly, Stephen, additional, Murphy, Michael P., additional, Powell, David R., additional, Barroso, Ines, additional, and Farooqi, I. Sadaf, additional

Published
2013
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34. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

Author

Azizan, Elena A B, primary, Poulsen, Hanne, additional, Tuluc, Petronel, additional, Zhou, Junhua, additional, Clausen, Michael V, additional, Lieb, Andreas, additional, Maniero, Carmela, additional, Garg, Sumedha, additional, Bochukova, Elena G, additional, Zhao, Wanfeng, additional, Shaikh, Lalarukh Haris, additional, Brighton, Cheryl A, additional, Teo, Ada E D, additional, Davenport, Anthony P, additional, Dekkers, Tanja, additional, Tops, Bas, additional, Küsters, Benno, additional, Ceral, Jiri, additional, Yeo, Giles S H, additional, Neogi, Sudeshna Guha, additional, McFarlane, Ian, additional, Rosenfeld, Nitzan, additional, Marass, Francesco, additional, Hadfield, James, additional, Margas, Wojciech, additional, Chaggar, Kanchan, additional, Solar, Miroslav, additional, Deinum, Jaap, additional, Dolphin, Annette C, additional, Farooqi, I Sadaf, additional, Striessnig, Joerg, additional, Nissen, Poul, additional, and Brown, Morris J, additional

Published
2013
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35. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity

Author

Wheeler, Eleanor, primary, Huang, Ni, additional, Bochukova, Elena G, additional, Keogh, Julia M, additional, Lindsay, Sarah, additional, Garg, Sumedha, additional, Henning, Elana, additional, Blackburn, Hannah, additional, Loos, Ruth J F, additional, Wareham, Nick J, additional, O'Rahilly, Stephen, additional, Hurles, Matthew E, additional, Barroso, Inês, additional, and Farooqi, I Sadaf, additional

Published
2013
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36. Auckland.

Author

Garg, Sumedha and el Shall, Esraa

Subjects
*BUSINESS mentorships, *CAREER development
Abstract

The article offers information on New Zealand Institute of Food Science and Technology Auckland Branch's annual Career Expo for all students in food science, food technology and all other food related disciplines held in Birkenhead and featured a number of food industry representatives along with the Auckland Branch Speed Mentoring event.

Published
2019

37. Regulation of aldosterone secretion by Cav1.3.

Author

Xie, Catherine B., Haris Shaikh, Lalarukh, Garg, Sumedha, Tanriver, Gizem, Teo, Ada E. D., Zhou, Junhua, Maniero, Carmela, Zhao, Wanfeng, Kang, Soosung, Silverman, Richard B., Azizan, Elena A. B., and Brown, Morris J.

Published
2016
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38. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity.

Author

Hendricks AE, Bochukova EG, Marenne G, Keogh JM, Atanassova N, Bounds R, Wheeler E, Mistry V, Henning E, Körner A, Muddyman D, McCarthy S, Hinney A, Hebebrand J, Scott RA, Langenberg C, Wareham NJ, Surendran P, Howson JM, Butterworth AS, Danesh J, Nordestgaard BG, Nielsen SF, Afzal S, Papadia S, Ashford S, Garg S, Millhauser GL, Palomino RI, Kwasniewska A, Tachmazidou I, O'Rahilly S, Zeggini E, Barroso I, and Farooqi IS

Subjects
Animals, Case-Control Studies, Chromogranins chemistry, Chromogranins genetics, Chromogranins metabolism, Female, GTP-Binding Protein alpha Subunits, Gs chemistry, GTP-Binding Protein alpha Subunits, Gs genetics, GTP-Binding Protein alpha Subunits, Gs metabolism, Humans, Male, Mice, Models, Molecular, Mutation, Obesity, Morbid diagnosis, Odds Ratio, Pediatric Obesity diagnosis, Pedigree, Protein Conformation, Rodentia, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Obesity, Morbid genetics, Pediatric Obesity genetics
Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 -3 ), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017
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