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1. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Author

Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu-Jie, Zanoni, Francesca, Liu, Lili, Mladkova, Nikol, Khan, Atlas, Marasa, Maddalena, Zhang, Jun Y., Balderes, Olivia, Sanna-Cherchi, Simone, Bomback, Andrew S., Canetta, Pietro A., Appel, Gerald B., Radhakrishnan, Jai, Trimarchi, Hernan, Sprangers, Ben, Cattran, Daniel C., Reich, Heather, Pei, York, Ravani, Pietro, Galesic, Kresimir, Maixnerova, Dita, Tesar, Vladimir, Stengel, Benedicte, Metzger, Marie, Canaud, Guillaume, Maillard, Nicolas, Berthoux, Francois, Berthelot, Laureline, Pillebout, Evangeline, Monteiro, Renato, Nelson, Raoul, Wyatt, Robert J., Smoyer, William, Mahan, John, Samhar, Al-Akash, Hidalgo, Guillermo, Quiroga, Alejandro, Weng, Patricia, Sreedharan, Raji, Selewski, David, Davis, Keefe, Kallash, Mahmoud, Vasylyeva, Tetyana L., Rheault, Michelle, Chishti, Aftab, Ranch, Daniel, Wenderfer, Scott E., Samsonov, Dmitry, Claes, Donna J., Akchurin, Oleh, Goumenos, Dimitrios, Stangou, Maria, Nagy, Judit, Kovacs, Tibor, Fiaccadori, Enrico, Amoroso, Antonio, Barlassina, Cristina, Cusi, Daniele, Del Vecchio, Lucia, Battaglia, Giovanni Giorgio, Bodria, Monica, Boer, Emanuela, Bono, Luisa, Boscutti, Giuliano, Caridi, Gianluca, Lugani, Francesca, Ghiggeri, GianMarco, Coppo, Rosanna, Peruzzi, Licia, Esposito, Vittoria, Esposito, Ciro, Feriozzi, Sandro, Polci, Rosaria, Frasca, Giovanni, Galliani, Marco, Garozzo, Maurizio, Mitrotti, Adele, Gesualdo, Loreto, Granata, Simona, Zaza, Gianluigi, Londrino, Francesco, Magistroni, Riccardo, Pisani, Isabella, Magnano, Andrea, Marcantoni, Carmelita, Messa, Piergiorgio, Mignani, Renzo, Pani, Antonello, Ponticelli, Claudio, Roccatello, Dario, Salvadori, Maurizio, Salvi, Erica, Santoro, Domenico, Gembillo, Guido, Savoldi, Silvana, Spotti, Donatella, Zamboli, Pasquale, Izzi, Claudia, Alberici, Federico, Delbarba, Elisa, Florczak, Michał, Krata, Natalia, Mucha, Krzysztof, Pączek, Leszek, Niemczyk, Stanisław, Moszczuk, Barbara, Pańczyk-Tomaszewska, Malgorzata, Mizerska-Wasiak, Malgorzata, Perkowska-Ptasińska, Agnieszka, Bączkowska, Teresa, Durlik, Magdalena, Pawlaczyk, Krzysztof, Sikora, Przemyslaw, Zaniew, Marcin, Kaminska, Dorota, Krajewska, Magdalena, Kuzmiuk-Glembin, Izabella, Heleniak, Zbigniew, Bullo-Piontecka, Barbara, Liberek, Tomasz, Dębska-Slizien, Alicja, Hryszko, Tomasz, Materna-Kiryluk, Anna, Miklaszewska, Monika, Szczepańska, Maria, Dyga, Katarzyna, Machura, Edyta, Siniewicz-Luzeńczyk, Katarzyna, Pawlak-Bratkowska, Monika, Tkaczyk, Marcin, Runowski, Dariusz, Kwella, Norbert, Drożdż, Dorota, Habura, Ireneusz, Kronenberg, Florian, Prikhodina, Larisa, van Heel, David, Fontaine, Bertrand, Cotsapas, Chris, Wijmenga, Cisca, Franke, Andre, Annese, Vito, Gregersen, Peter K., Parameswaran, Sreeja, Weirauch, Matthew, Kottyan, Leah, Harley, John B., Suzuki, Hitoshi, Narita, Ichiei, Goto, Shin, Lee, Hajeong, Kim, Dong Ki, Kim, Yon Su, Park, Jin-Ho, Cho, BeLong, Choi, Murim, Van Wijk, Ans, Huerta, Ana, Ars, Elisabet, Ballarin, Jose, Lundberg, Sigrid, Vogt, Bruno, Mani, Laila-Yasmin, Caliskan, Yasar, Barratt, Jonathan, Abeygunaratne, Thilini, Kalra, Philip A., Gale, Daniel P., Panzer, Ulf, Rauen, Thomas, Floege, Jürgen, Schlosser, Pascal, Ekici, Arif B., Eckardt, Kai-Uwe, Chen, Nan, Xie, Jingyuan, Lifton, Richard P., Loos, Ruth J. F., Kenny, Eimear E., Ionita-Laza, Iuliana, Köttgen, Anna, Julian, Bruce A., Novak, Jan, Scolari, Francesco, Zhang, Hong, and Gharavi, Ali G.

Published
2023
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2. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Author

Jin, Sheng Chih, Homsy, Jason, Zaidi, Samir, Lu, Qiongshi, Morton, Sarah, DePalma, Steven R, Zeng, Xue, Qi, Hongjian, Chang, Weni, Sierant, Michael C, Hung, Wei-Chien, Haider, Shozeb, Zhang, Junhui, Knight, James, Bjornson, Robert D, Castaldi, Christopher, Tikhonoa, Irina R, Bilguvar, Kaya, Mane, Shrikant M, Sanders, Stephan J, Mital, Seema, Russell, Mark W, Gaynor, J William, Deanfield, John, Giardini, Alessandro, Porter, George A, Srivastava, Deepak, Lo, Cecelia W, Shen, Yufeng, Watkins, W Scott, Yandell, Mark, Yost, H Joseph, Tristani-Firouzi, Martin, Newburger, Jane W, Roberts, Amy E, Kim, Richard, Zhao, Hongyu, Kaltman, Jonathan R, Goldmuntz, Elizabeth, Chung, Wendy K, Seidman, Jonathan G, Gelb, Bruce D, Seidman, Christine E, Lifton, Richard P, and Brueckner, Martina

Subjects
Biological Sciences, Genetics, Cardiovascular, Pediatric, Congenital Structural Anomalies, Brain Disorders, Heart Disease, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Published
2017

3. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Author

Jin, Sheng Chih, Lewis, Sara A., Bakhtiari, Somayeh, Zeng, Xue, Sierant, Michael C., Shetty, Sheetal, Nordlie, Sandra M., Elie, Aureliane, Corbett, Mark A., Norton, Bethany Y., van Eyk, Clare L., Haider, Shozeb, Guida, Brandon S., Magee, Helen, Liu, James, Pastore, Stephen, Vincent, John B., Brunstrom-Hernandez, Janice, Papavasileiou, Antigone, Fahey, Michael C., Berry, Jesia G., Harper, Kelly, Zhou, Chongchen, Zhang, Junhui, Li, Boyang, Zhao, Hongyu, Heim, Jennifer, Webber, Dani L., Frank, Mahalia S. B., Xia, Lei, Xu, Yiran, Zhu, Dengna, Zhang, Bohao, Sheth, Amar H., Knight, James R., Castaldi, Christopher, Tikhonova, Irina R., López-Giráldez, Francesc, Keren, Boris, Whalen, Sandra, Buratti, Julien, Doummar, Diane, Cho, Megan, Retterer, Kyle, Millan, Francisca, Wang, Yangong, Waugh, Jeff L., Rodan, Lance, Cohen, Julie S., Fatemi, Ali, Lin, Angela E., Phillips, John P., Feyma, Timothy, MacLennan, Suzanna C., Vaughan, Spencer, Crompton, Kylie E., Reid, Susan M., Reddihough, Dinah S., Shang, Qing, Gao, Chao, Novak, Iona, Badawi, Nadia, Wilson, Yana A., McIntyre, Sarah J., Mane, Shrikant M., Wang, Xiaoyang, Amor, David J., Zarnescu, Daniela C., Lu, Qiongshi, Xing, Qinghe, Zhu, Changlian, Bilguvar, Kaya, Padilla-Lopez, Sergio, Lifton, Richard P., Gecz, Jozef, MacLennan, Alastair H., and Kruer, Michael C.

Published
2020
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4. CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Author

Esteghamat, Fatemehsadat, Broughton, James S., Smith, Emily, Cardone, Rebecca, Tyagi, Tarun, Guerra, Mateus, Szabó, András, Ugwu, Nelson, Mani, Mitra V., Azari, Bani, Kayingo, Gerald, Chung, Sunny, Fathzadeh, Mohsen, Weiss, Ephraim, Bender, Jeffrey, Mane, Shrikant, Lifton, Richard P., Adeniran, Adebowale, Nathanson, Michael H., Gorelick, Fred S., Hwa, John, Sahin-Tóth, Miklós, Belfort-DeAguiar, Renata, Kibbey, Richard G., and Mani, Arya

Published
2019
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5. CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Author

Scholl, Ute I., Stölting, Gabriel, Schewe, Julia, Thiel, Anne, Tan, Hua, Nelson-Williams, Carol, Vichot, Alfred A., Jin, Sheng Chih, Loring, Erin, Untiet, Verena, Yoo, Taekyeong, Choi, Jungmin, Xu, Shengxin, Wu, Aihua, Kirchner, Marieluise, Mertins, Philipp, Rump, Lars C., Onder, Ali Mirza, Gamble, Cory, McKenney, Daniel, Lash, Robert W., Jones, Deborah P., Chune, Gary, Gagliardi, Priscila, Choi, Murim, Gordon, Richard, Stowasser, Michael, Fahlke, Christoph, and Lifton, Richard P.

Published
2018
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6. Author Correction: Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Author

Jin, Sheng Chih, Lewis, Sara A., Bakhtiari, Somayeh, Zeng, Xue, Sierant, Michael C., Shetty, Sheetal, Nordlie, Sandra M., Elie, Aureliane, Corbett, Mark A., Norton, Bethany Y., van Eyk, Clare L., Haider, Shozeb, Guida, Brandon S., Magee, Helen, Liu, James, Pastore, Stephen, Vincent, John B., Brunstrom-Hernandez, Janice, Papavasileiou, Antigone, Fahey, Michael C., Berry, Jesia G., Harper, Kelly, Zhou, Chongchen, Zhang, Junhui, Li, Boyang, Zhao, Hongyu, Heim, Jennifer, Webber, Dani L., Frank, Mahalia S. B., Xia, Lei, Xu, Yiran, Zhu, Dengna, Zhang, Bohao, Sheth, Amar H., Knight, James R., Castaldi, Christopher, Tikhonova, Irina R., López-Giráldez, Francesc, Keren, Boris, Whalen, Sandra, Buratti, Julien, Doummar, Diane, Cho, Megan, Retterer, Kyle, Millan, Francisca, Wang, Yangong, Waugh, Jeff L., Rodan, Lance, Cohen, Julie S., Fatemi, Ali, Lin, Angela E., Phillips, John P., Feyma, Timothy, MacLennan, Suzanna C., Vaughan, Spencer, Crompton, Kylie E., Reid, Susan M., Reddihough, Dinah S., Shang, Qing, Gao, Chao, Novak, Iona, Badawi, Nadia, Wilson, Yana A., McIntyre, Sarah J., Mane, Shrikant M., Wang, Xiaoyang, Amor, David J., Zarnescu, Daniela C., Lu, Qiongshi, Xing, Qinghe, Zhu, Changlian, Bilguvar, Kaya, Padilla-Lopez, Sergio, Lifton, Richard P., Gecz, Jozef, MacLennan, Alastair H., and Kruer, Michael C.

Published
2021
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7. Genomic landscape of cutaneous T cell lymphoma

Author

Choi, Jaehyuk, Goh, Gerald, Walradt, Trent, Hong, Bok S, Bunick, Christopher G, Chen, Kan, Bjornson, Robert D, Maman, Yaakov, Wang, Tiffany, Tordoff, Jesse, Carlson, Kacie, Overton, John D, Liu, Kristina J, Lewis, Julia M, Devine, Lesley, Barbarotta, Lisa, Foss, Francine M, Subtil, Antonio, Vonderheid, Eric C, Edelson, Richard L, Schatz, David G, Boggon, Titus J, Girardi, Michael, and Lifton, Richard P

Published
2015
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10. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

Author

Krauthammer, Michael, Kong, Yong, Ha, Byung Hak, Evans, Perry, Bacchiocchi, Antonella, McCusker, Jamie P, Cheng, Elaine, Davis, Matthew J, Goh, Gerald, Choi, Murim, Ariyan, Stephan, Narayan, Deepak, Dutton-Regester, Ken, Capatana, Ana, Holman, Edna C, Bosenberg, Marcus, Sznol, Mario, Kluger, Harriet M, Brash, Douglas E, Stern, David F, Materin, Miguel A, Lo, Roger S, Mane, Shrikant, Ma, Shuangge, Kidd, Kenneth K, Hayward, Nicholas K, Lifton, Richard P, Schlessinger, Joseph, Boggon, Titus J, and Halaban, Ruth

Published
2012
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12. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Author

Braun, Daniela A, primary, Rao, Jia, additional, Mollet, Geraldine, additional, Schapiro, David, additional, Daugeron, Marie-Claire, additional, Tan, Weizhen, additional, Gribouval, Olivier, additional, Boyer, Olivia, additional, Revy, Patrick, additional, Jobst-Schwan, Tilman, additional, Schmidt, Johanna Magdalena, additional, Lawson, Jennifer A, additional, Schanze, Denny, additional, Ashraf, Shazia, additional, Ullmann, Jeremy F P, additional, Hoogstraten, Charlotte A, additional, Boddaert, Nathalie, additional, Collinet, Bruno, additional, Martin, Gaëlle, additional, Liger, Dominique, additional, Lovric, Svjetlana, additional, Furlano, Monica, additional, Guerrera, I Chiara, additional, Sanchez-Ferras, Oraly, additional, Hu, Jennifer F, additional, Boschat, Anne-Claire, additional, Sanquer, Sylvia, additional, Menten, Björn, additional, Vergult, Sarah, additional, De Rocker, Nina, additional, Airik, Merlin, additional, Hermle, Tobias, additional, Shril, Shirlee, additional, Widmeier, Eugen, additional, Gee, Heon Yung, additional, Choi, Won-Il, additional, Sadowski, Carolin E, additional, Pabst, Werner L, additional, Warejko, Jillian K, additional, Daga, Ankana, additional, Basta, Tamara, additional, Matejas, Verena, additional, Scharmann, Karin, additional, Kienast, Sandra D, additional, Behnam, Babak, additional, Beeson, Brendan, additional, Begtrup, Amber, additional, Bruce, Malcolm, additional, Ch'ng, Gaik-Siew, additional, Lin, Shuan-Pei, additional, Chang, Jui-Hsing, additional, Chen, Chao-Huei, additional, Cho, Megan T, additional, Gaffney, Patrick M, additional, Gipson, Patrick E, additional, Hsu, Chyong-Hsin, additional, Kari, Jameela A, additional, Ke, Yu-Yuan, additional, Kiraly-Borri, Cathy, additional, Lai, Wai-ming, additional, Lemyre, Emmanuelle, additional, Littlejohn, Rebecca Okashah, additional, Masri, Amira, additional, Moghtaderi, Mastaneh, additional, Nakamura, Kazuyuki, additional, Ozaltin, Fatih, additional, Praet, Marleen, additional, Prasad, Chitra, additional, Prytula, Agnieszka, additional, Roeder, Elizabeth R, additional, Rump, Patrick, additional, Schnur, Rhonda E, additional, Shiihara, Takashi, additional, Sinha, Manish D, additional, Soliman, Neveen A, additional, Soulami, Kenza, additional, Sweetser, David A, additional, Tsai, Wen-Hui, additional, Tsai, Jeng-Daw, additional, Topaloglu, Rezan, additional, Vester, Udo, additional, Viskochil, David H, additional, Vatanavicharn, Nithiwat, additional, Waxler, Jessica L, additional, Wierenga, Klaas J, additional, Wolf, Matthias T F, additional, Wong, Sik-Nin, additional, Leidel, Sebastian A, additional, Truglio, Gessica, additional, Dedon, Peter C, additional, Poduri, Annapurna, additional, Mane, Shrikant, additional, Lifton, Richard P, additional, Bouchard, Maxime, additional, Kannu, Peter, additional, Chitayat, David, additional, Magen, Daniella, additional, Callewaert, Bert, additional, van Tilbeurgh, Herman, additional, Zenker, Martin, additional, Antignac, Corinne, additional, and Hildebrandt, Friedhelm, additional

Published
2017
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13. Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome

Author

Braun, Daniela A, primary, Sadowski, Carolin E, additional, Kohl, Stefan, additional, Lovric, Svjetlana, additional, Astrinidis, Susanne A, additional, Pabst, Werner L, additional, Gee, Heon Yung, additional, Ashraf, Shazia, additional, Lawson, Jennifer A, additional, Shril, Shirlee, additional, Airik, Merlin, additional, Tan, Weizhen, additional, Schapiro, David, additional, Rao, Jia, additional, Choi, Won-Il, additional, Hermle, Tobias, additional, Kemper, Markus J, additional, Pohl, Martin, additional, Ozaltin, Fatih, additional, Konrad, Martin, additional, Bogdanovic, Radovan, additional, Büscher, Rainer, additional, Helmchen, Udo, additional, Serdaroglu, Erkin, additional, Lifton, Richard P, additional, Antonin, Wolfram, additional, and Hildebrandt, Friedhelm, additional

Published
2016
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14. CELA2Amutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Author

Esteghamat, Fatemehsadat, Broughton, James, Smith, Emily, Cardone, Rebecca, Tyagi, Tarun, Guerra, Mateus, Szabó, András, Ugwu, Nelson, Mani, Mitra, Azari, Bani, Kayingo, Gerald, Chung, Sunny, Fathzadeh, Mohsen, Weiss, Ephraim, Bender, Jeffrey, Mane, Shrikant, Lifton, Richard, Adeniran, Adebowale, Nathanson, Michael, Gorelick, Fred, Hwa, John, Sahin-Tóth, Miklós, Belfort-DeAguiar, Renata, Kibbey, Richard, and Mani, Arya

Abstract

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target. Exome sequencing identifies loss-of-function CELA2Amutations in families with early-onset atherosclerosis and metabolic syndrome. Functional studies show that CELA2A is a circulating enzyme that reduces platelet activation, triggers insulin secretion and degradation, and increases insulin sensitivity.

Published
2019
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15. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Author

Stuart, Bridget D, primary, Choi, Jungmin, additional, Zaidi, Samir, additional, Xing, Chao, additional, Holohan, Brody, additional, Chen, Rui, additional, Choi, Mihwa, additional, Dharwadkar, Pooja, additional, Torres, Fernando, additional, Girod, Carlos E, additional, Weissler, Jonathan, additional, Fitzgerald, John, additional, Kershaw, Corey, additional, Klesney-Tait, Julia, additional, Mageto, Yolanda, additional, Shay, Jerry W, additional, Ji, Weizhen, additional, Bilguvar, Kaya, additional, Mane, Shrikant, additional, Lifton, Richard P, additional, and Garcia, Christine Kim, additional

Published
2015
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16. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

Author

Kiryluk, Krzysztof, primary, Li, Yifu, additional, Scolari, Francesco, additional, Sanna-Cherchi, Simone, additional, Choi, Murim, additional, Verbitsky, Miguel, additional, Fasel, David, additional, Lata, Sneh, additional, Prakash, Sindhuri, additional, Shapiro, Samantha, additional, Fischman, Clara, additional, Snyder, Holly J, additional, Appel, Gerald, additional, Izzi, Claudia, additional, Viola, Battista Fabio, additional, Dallera, Nadia, additional, Del Vecchio, Lucia, additional, Barlassina, Cristina, additional, Salvi, Erika, additional, Bertinetto, Francesca Eleonora, additional, Amoroso, Antonio, additional, Savoldi, Silvana, additional, Rocchietti, Marcella, additional, Amore, Alessandro, additional, Peruzzi, Licia, additional, Coppo, Rosanna, additional, Salvadori, Maurizio, additional, Ravani, Pietro, additional, Magistroni, Riccardo, additional, Ghiggeri, Gian Marco, additional, Caridi, Gianluca, additional, Bodria, Monica, additional, Lugani, Francesca, additional, Allegri, Landino, additional, Delsante, Marco, additional, Maiorana, Mariarosa, additional, Magnano, Andrea, additional, Frasca, Giovanni, additional, Boer, Emanuela, additional, Boscutti, Giuliano, additional, Ponticelli, Claudio, additional, Mignani, Renzo, additional, Marcantoni, Carmelita, additional, Di Landro, Domenico, additional, Santoro, Domenico, additional, Pani, Antonello, additional, Polci, Rosaria, additional, Feriozzi, Sandro, additional, Chicca, Silvana, additional, Galliani, Marco, additional, Gigante, Maddalena, additional, Gesualdo, Loreto, additional, Zamboli, Pasquale, additional, Battaglia, Giovanni Giorgio, additional, Garozzo, Maurizio, additional, Maixnerová, Dita, additional, Tesar, Vladimir, additional, Eitner, Frank, additional, Rauen, Thomas, additional, Floege, Jürgen, additional, Kovacs, Tibor, additional, Nagy, Judit, additional, Mucha, Krzysztof, additional, Pączek, Leszek, additional, Zaniew, Marcin, additional, Mizerska-Wasiak, Małgorzata, additional, Roszkowska-Blaim, Maria, additional, Pawlaczyk, Krzysztof, additional, Gale, Daniel, additional, Barratt, Jonathan, additional, Thibaudin, Lise, additional, Berthoux, Francois, additional, Canaud, Guillaume, additional, Boland, Anne, additional, Metzger, Marie, additional, Panzer, Ulf, additional, Suzuki, Hitoshi, additional, Goto, Shin, additional, Narita, Ichiei, additional, Caliskan, Yasar, additional, Xie, Jingyuan, additional, Hou, Ping, additional, Chen, Nan, additional, Zhang, Hong, additional, Wyatt, Robert J, additional, Novak, Jan, additional, Julian, Bruce A, additional, Feehally, John, additional, Stengel, Benedicte, additional, Cusi, Daniele, additional, Lifton, Richard P, additional, and Gharavi, Ali G, additional

Published
2014
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17. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

Author

Romberg, Neil, primary, Al Moussawi, Khatoun, additional, Nelson-Williams, Carol, additional, Stiegler, Amy L, additional, Loring, Erin, additional, Choi, Murim, additional, Overton, John, additional, Meffre, Eric, additional, Khokha, Mustafa K, additional, Huttner, Anita J, additional, West, Brian, additional, Podoltsev, Nikolai A, additional, Boggon, Titus J, additional, Kazmierczak, Barbara I, additional, and Lifton, Richard P, additional

Published
2014
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18. CLCN2chloride channel mutations in familial hyperaldosteronism type II

Author

Scholl, Ute, Stölting, Gabriel, Schewe, Julia, Thiel, Anne, Tan, Hua, Nelson-Williams, Carol, Vichot, Alfred, Jin, Sheng, Loring, Erin, Untiet, Verena, Yoo, Taekyeong, Choi, Jungmin, Xu, Shengxin, Wu, Aihua, Kirchner, Marieluise, Mertins, Philipp, Rump, Lars, Onder, Ali, Gamble, Cory, McKenney, Daniel, Lash, Robert, Jones, Deborah, Chune, Gary, Gagliardi, Priscila, Choi, Murim, Gordon, Richard, Stowasser, Michael, Fahlke, Christoph, and Lifton, Richard

Abstract

Primary aldosteronism, a common cause of severe hypertension1 , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2variant found in the proband. CLCN2encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism. Whole-exome sequencing identifies mutations in CLCN2in individuals with familial hyperaldosteronism type II or early-onset primary aldosteronism. These gain-of-function mutations cause chloride channel opening and glomerulosa cell depolarization, showing a role for anion channels in aldosterone production.

Published
2018
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19. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism

Author

Scholl, Ute I, primary, Goh, Gerald, additional, Stölting, Gabriel, additional, de Oliveira, Regina Campos, additional, Choi, Murim, additional, Overton, John D, additional, Fonseca, Annabelle L, additional, Korah, Reju, additional, Starker, Lee F, additional, Kunstman, John W, additional, Prasad, Manju L, additional, Hartung, Erum A, additional, Mauras, Nelly, additional, Benson, Matthew R, additional, Brady, Tammy, additional, Shapiro, Jay R, additional, Loring, Erin, additional, Nelson-Williams, Carol, additional, Libutti, Steven K, additional, Mane, Shrikant, additional, Hellman, Per, additional, Westin, Gunnar, additional, Åkerström, Göran, additional, Björklund, Peyman, additional, Carling, Tobias, additional, Fahlke, Christoph, additional, Hidalgo, Patricia, additional, and Lifton, Richard P, additional

Published
2013
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20. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Author

Lemaire, Mathieu, primary, Frémeaux-Bacchi, Véronique, additional, Schaefer, Franz, additional, Choi, Murim, additional, Tang, Wai Ho, additional, Le Quintrec, Moglie, additional, Fakhouri, Fadi, additional, Taque, Sophie, additional, Nobili, François, additional, Martinez, Frank, additional, Ji, Weizhen, additional, Overton, John D, additional, Mane, Shrikant M, additional, Nürnberg, Gudrun, additional, Altmüller, Janine, additional, Thiele, Holger, additional, Morin, Denis, additional, Deschenes, Georges, additional, Baudouin, Véronique, additional, Llanas, Brigitte, additional, Collard, Laure, additional, Majid, Mohammed A, additional, Simkova, Eva, additional, Nürnberg, Peter, additional, Rioux-Leclerc, Nathalie, additional, Moeckel, Gilbert W, additional, Gubler, Marie Claire, additional, Hwa, John, additional, Loirat, Chantal, additional, and Lifton, Richard P, additional

Published
2013
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21. Recessive LAMC3 mutations cause malformations of occipital cortical development

Author

Barak, Tanyeri, primary, Kwan, Kenneth Y, additional, Louvi, Angeliki, additional, Demirbilek, Veysi, additional, Saygı, Serap, additional, Tüysüz, Beyhan, additional, Choi, Murim, additional, Boyacı, Hüseyin, additional, Doerschner, Katja, additional, Zhu, Ying, additional, Kaymakçalan, Hande, additional, Yılmaz, Saliha, additional, Bakırcıoğlu, Mehmet, additional, Çağlayan, Ahmet Okay, additional, Öztürk, Ali Kemal, additional, Yasuno, Katsuhito, additional, Brunken, William J, additional, Atalar, Ergin, additional, Yalçınkaya, Cengiz, additional, Dinçer, Alp, additional, Bronen, Richard A, additional, Mane, Shrikant, additional, Özçelik, Tayfun, additional, Lifton, Richard P, additional, Šestan, Nenad, additional, Bilgüvar, Kaya, additional, and Günel, Murat, additional

Published
2011
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22. Genome-wide association study identifies susceptibility loci for IgA nephropathy

Author

Gharavi, Ali G, primary, Kiryluk, Krzysztof, additional, Choi, Murim, additional, Li, Yifu, additional, Hou, Ping, additional, Xie, Jingyuan, additional, Sanna-Cherchi, Simone, additional, Men, Clara J, additional, Julian, Bruce A, additional, Wyatt, Robert J, additional, Novak, Jan, additional, He, John C, additional, Wang, Haiyan, additional, Lv, Jicheng, additional, Zhu, Li, additional, Wang, Weiming, additional, Wang, Zhaohui, additional, Yasuno, Kasuhito, additional, Gunel, Murat, additional, Mane, Shrikant, additional, Umlauf, Sheila, additional, Tikhonova, Irina, additional, Beerman, Isabel, additional, Savoldi, Silvana, additional, Magistroni, Riccardo, additional, Ghiggeri, Gian Marco, additional, Bodria, Monica, additional, Lugani, Francesca, additional, Ravani, Pietro, additional, Ponticelli, Claudio, additional, Allegri, Landino, additional, Boscutti, Giuliano, additional, Frasca, Giovanni, additional, Amore, Alessandro, additional, Peruzzi, Licia, additional, Coppo, Rosanna, additional, Izzi, Claudia, additional, Viola, Battista Fabio, additional, Prati, Elisabetta, additional, Salvadori, Maurizio, additional, Mignani, Renzo, additional, Gesualdo, Loreto, additional, Bertinetto, Francesca, additional, Mesiano, Paola, additional, Amoroso, Antonio, additional, Scolari, Francesco, additional, Chen, Nan, additional, Zhang, Hong, additional, and Lifton, Richard P, additional

Published
2011
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23. Genome-wide association study of intracranial aneurysm identifies three new risk loci

Author

Yasuno, Katsuhito, primary, Bilguvar, Kaya, additional, Bijlenga, Philippe, additional, Low, Siew-Kee, additional, Krischek, Boris, additional, Auburger, Georg, additional, Simon, Matthias, additional, Krex, Dietmar, additional, Arlier, Zulfikar, additional, Nayak, Nikhil, additional, Ruigrok, Ynte M, additional, Niemelä, Mika, additional, Tajima, Atsushi, additional, von und zu Fraunberg, Mikael, additional, Dóczi, Tamás, additional, Wirjatijasa, Florentina, additional, Hata, Akira, additional, Blasco, Jordi, additional, Oszvald, Agi, additional, Kasuya, Hidetoshi, additional, Zilani, Gulam, additional, Schoch, Beate, additional, Singh, Pankaj, additional, Stüer, Carsten, additional, Risselada, Roelof, additional, Beck, Jürgen, additional, Sola, Teresa, additional, Ricciardi, Filomena, additional, Aromaa, Arpo, additional, Illig, Thomas, additional, Schreiber, Stefan, additional, van Duijn, Cornelia M, additional, van den Berg, Leonard H, additional, Perret, Claire, additional, Proust, Carole, additional, Roder, Constantin, additional, Ozturk, Ali K, additional, Gaál, Emília, additional, Berg, Daniela, additional, Geisen, Christof, additional, Friedrich, Christoph M, additional, Summers, Paul, additional, Frangi, Alejandro F, additional, State, Matthew W, additional, Wichmann, H Erich, additional, Breteler, Monique M B, additional, Wijmenga, Cisca, additional, Mane, Shrikant, additional, Peltonen, Leena, additional, Elio, Vivas, additional, Sturkenboom, Miriam C J M, additional, Lawford, Patricia, additional, Byrne, James, additional, Macho, Juan, additional, Sandalcioglu, Erol I, additional, Meyer, Bernhard, additional, Raabe, Andreas, additional, Steinmetz, Helmuth, additional, Rüfenacht, Daniel, additional, Jääskeläinen, Juha E, additional, Hernesniemi, Juha, additional, Rinkel, Gabriel J E, additional, Zembutsu, Hitoshi, additional, Inoue, Ituro, additional, Palotie, Aarno, additional, Cambien, François, additional, Nakamura, Yusuke, additional, Lifton, Richard P, additional, and Günel, Murat, additional

Published
2010
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24. Susceptibility loci for intracranial aneurysm in European and Japanese populations

Author

Bilguvar, Kaya, primary, Yasuno, Katsuhito, additional, Niemelä, Mika, additional, Ruigrok, Ynte M, additional, von und zu Fraunberg, Mikael, additional, van Duijn, Cornelia M, additional, van den Berg, Leonard H, additional, Mane, Shrikant, additional, Mason, Christopher E, additional, Choi, Murim, additional, Gaál, Emília, additional, Bayri, Yasar, additional, Kolb, Luis, additional, Arlier, Zulfikar, additional, Ravuri, Sudhakar, additional, Ronkainen, Antti, additional, Tajima, Atsushi, additional, Laakso, Aki, additional, Hata, Akira, additional, Kasuya, Hidetoshi, additional, Koivisto, Timo, additional, Rinne, Jaakko, additional, Öhman, Juha, additional, Breteler, Monique M B, additional, Wijmenga, Cisca, additional, State, Matthew W, additional, Rinkel, Gabriel J E, additional, Hernesniemi, Juha, additional, Jääskeläinen, Juha E, additional, Palotie, Aarno, additional, Inoue, Ituro, additional, Lifton, Richard P, additional, and Günel, Murat, additional

Published
2008
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26. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.

Author

Lifton, Richard P, Cheng, Elaine, Halaban, Ruth, McCusker, James P, Ma, Shuangge, Sznol, Mario, Krauthammer, Michael, Serin, Merdan, Evans, Perry, Mane, Shrikant, Bacchiocchi, Antonella, Pornputtapong, Natapol, Narayan, Deepak, Kluger, Harriet M, Bosenberg, Marcus, Kong, Yong, Wu, Cen, Ariyan, Stephan, Schlessinger, Joseph, and Straub, Robert

Subjects
*MELANOMA, *NEUROFIBROMIN, *RAS oncogenes, *BRAF genes, *GUANOSINE triphosphatase
Abstract

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis. [ABSTRACT FROM AUTHOR]

Published
2015
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27. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

Author

Lalioti, Maria D, primary, Zhang, Junhui, additional, Volkman, Heather M, additional, Kahle, Kristopher T, additional, Hoffmann, Kristin E, additional, Toka, Hakan R, additional, Nelson-Williams, Carol, additional, Ellison, David H, additional, Flavell, Richard, additional, Booth, Carmen J, additional, Lu, Yin, additional, Geller, David S, additional, and Lifton, Richard P, additional

Published
2006
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28. Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia

Author

Bonnen, Penelope E, primary, Pe'er, Itsik, additional, Plenge, Robert M, additional, Salit, Jackie, additional, Lowe, Jennifer K, additional, Shapero, Michael H, additional, Lifton, Richard P, additional, Breslow, Jan L, additional, Daly, Mark J, additional, Reich, David E, additional, Jones, Keith W, additional, Stoffel, Markus, additional, Altshuler, David, additional, and Friedman, Jeffrey M, additional

Published
2006
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29. Mutations in SEC63 cause autosomal dominant polycystic liver disease

Author

Davila, Sonia, primary, Furu, Laszlo, additional, Gharavi, Ali G, additional, Tian, Xin, additional, Onoe, Tamehito, additional, Qian, Qi, additional, Li, Airong, additional, Cai, Yiqiang, additional, Kamath, Patrick S, additional, King, Bernard F, additional, Azurmendi, Pablo J, additional, Tahvanainen, Pia, additional, Kääriäinen, Helena, additional, Höckerstedt, Krister, additional, Devuyst, Olivier, additional, Pirson, Yves, additional, Martin, Rodolfo S, additional, Lifton, Richard P, additional, Tahvanainen, Esa, additional, Torres, Vicente E, additional, and Somlo, Stefan, additional

Published
2004
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30. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

Author

Kahle, Kristopher T, primary, Wilson, Frederick H, additional, Leng, Qiang, additional, Lalioti, Maria D, additional, O'Connell, Anthony D, additional, Dong, Ke, additional, Rapson, Alicia K, additional, MacGregor, Gordon G, additional, Giebisch, Gerhard, additional, Hebert, Steven C, additional, and Lifton, Richard P, additional

Published
2003
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31. IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22–23

Author

Gharavi, Ali G., primary, Yan, Yan, additional, Scolari, Francesco, additional, Schena, F. Paolo, additional, Frasca, Giovanni M., additional, Ghiggeri, Gian Marco, additional, Cooper, Kerry, additional, Amoroso, Antonio, additional, Viola, Battista Fabio, additional, Battini, Graziana, additional, Caridi, Gianluca, additional, Canova, Cristina, additional, Farhi, Anita, additional, Subramanian, Vairavan, additional, Nelson-Williams, Carol, additional, Woodford, Sue, additional, Julian, Bruce A., additional, Wyatt, Robert J., additional, and Lifton, Richard P., additional

Published
2000
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32. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing

Author

Smith, Annabel N., primary, Skaug, Jennifer, additional, Choate, Keith A., additional, Nayir, Ahmet, additional, Bakkaloglu, Aysin, additional, Ozen, Seza, additional, Hulton, Sally A., additional, Sanjad, Sami A., additional, Al-Sabban, Essam A., additional, Lifton, Richard P., additional, Scherer, Stephen W., additional, and Karet, Fiona E., additional

Published
2000
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33. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness

Author

Karet, Fiona E., primary, Finberg, Karin E., additional, Nelson, Raoul D., additional, Nayir, Ahmet, additional, Mocan, Hilal, additional, Sanjad, Sami A., additional, Rodriguez-Soriano, Juan, additional, Santos, Fernando, additional, Cremers, Cor W.R.J., additional, Pietro, Antonio Di, additional, Hoffbrand, Barry I., additional, Winiarski, Jacek, additional, Bakkaloglu, Aysin, additional, Ozen, Seza, additional, Dusunsel, Ruhan, additional, Goodyer, Paul, additional, Hulton, Sally A., additional, Wu, Doris K., additional, Skvorak, Anne B., additional, Morton, Cynthia C., additional, Cunningham, Michael J., additional, Jha, Vivekanand, additional, and Lifton, Richard P., additional

Published
1999
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35. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III

Author

Simon, David B., primary, Bindra, Ranjit S., additional, Mansfield, Traci A., additional, Nelson-Williams, Carol, additional, Mendonca, Erica, additional, Stone, Rosário, additional, Schurman, Scott, additional, Nayir, Ahmet, additional, Alpay, Harika, additional, Bakkaloglu, Aysin, additional, Rodriguez-Soriano, Juan, additional, Morales, Jose M., additional, Sanjad, Sami A., additional, Taylor, C. Mark, additional, Pilz, Daniela, additional, Brem, Andrew, additional, Trachtman, Howard, additional, Griswold, William, additional, Richard, George A., additional, John, Eunice, additional, and Lifton, Richard P., additional

Published
1997
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36. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21

Author

Mansfield, Traci A., primary, Simon, David B., additional, Farfel, Zvi, additional, Bia, Margaret, additional, Tucci, Joseph R., additional, Lebe, Marcel, additional, Gutkin, Michael, additional, Vialettes, Bernard, additional, Christofilis, Marie A., additional, Kauppinen-Makelin, Ritva, additional, Mayan, Haim, additional, Risch, Neil, additional, and Lifton, Richard P., additional

Published
1997
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40. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1

Author

Chang, Sue S., primary, Grunder, Stefan, additional, Hanukoglu, Aaron, additional, Rösler, Ariel, additional, Mathew, P.M., additional, Hanukoglu, Israel, additional, Schild, Laurent, additional, Lu, Yin, additional, Shimkets, Richard A., additional, Nelson-Williams, Carol, additional, Rossier, Bernard C., additional, and Lifton, Richard P., additional

Published
1996
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41. Gitelman's variant of Barter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter

Author

Simon, David B., primary, Nelson-Williams, Carol, additional, Johnson Bia, Margaret, additional, Ellison, David, additional, Karet, Fiona E., additional, Morey Molina, Antonio, additional, Vaara, Ivar, additional, Iwata, Fujihiko, additional, Cushner, Howard M., additional, Koolen, Marianne, additional, Gainza, Francisco J., additional, Gitelman, Hillel J., additional, and Lifton, Richard P., additional

Published
1996
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43. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase

Author

Lifton, Richard P., primary, Dluhy, Robert G., additional, Powers, Michael, additional, Rich, Glenn M., additional, Gutkin, Michael, additional, Fallo, Francesco, additional, Gill, John R., additional, Feld, Leonard, additional, Ganguly, Arunabha, additional, Laidlaw, Jack C., additional, Murnaghan, D.J., additional, Kaufman, Chris, additional, Stockigt, Jan R., additional, Ulick, Stanley, additional, and Lalouel, Jean-Marc, additional

Published
1992
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45. Rare independent mutations in renal salt handling genes contribute to blood pressure variation.

Author

Weizhen Ji, Jia Nee Foo, O'Roak, Brian J., Hongyu Zhao, Larson, Martin G., Simon, David B., Newton-Cheh, Christopher, State, Matthew W., Levy, Daniel, and Lifton, Richard P.

Subjects
GENETIC mutation, MOLECULAR genetics, HYPERTENSION, BLOOD pressure, GENOMICS, GENETIC research
Abstract

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes—SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)—causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits. [ABSTRACT FROM AUTHOR]

Published
2008
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46. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.

Author

Lalioti, Maria D., Qiang Leng, O'Connell, Anthony D., Ke Dong, Rapson, Alicia K., MacGregor, Gordon G., Giebisch, Gerhard, Hebert, Steven C., Lifton, Richard P., Kahle, Kristopher T., and Wilson, Frederick H.

Subjects
REGULATION of biological transport, ABSORPTION (Physiology), PHYSIOLOGICAL effects of salt, POTASSIUM in the body, GENETIC engineering, HOMEOSTASIS, RENAL hypertension, BLOOD pressure
Abstract

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration (refs. 2,3). Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. [ABSTRACT FROM AUTHOR]

Published
2003
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48. Genetic heterogeneity of Barter's syndrome revealed by mutations in the K+channel, ROMK

Author

Simon, David B., Karet, Fiona E., Rodriguez-Soriano, Juan, Hamdan, Jahed H., DiPietro, Antonio, Trachtman, Howard, Sanjad, Sami A., and Lifton, Richard P.

Abstract

Mutations in the Na–K–2CI cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Barrier's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP–sensitive K+channel that ‘recycles’ reabsorbed K+back to the tubule lumen. Examination of the ROMK gene reveals mutations that co–segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.

Published
1996
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49. Rare independent mutations in renal salt handling genes contribute to blood pressure variation.

Author

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, and Lifton RP

Subjects
Adult, Amino Acid Sequence, Amino Acid Substitution, Cohort Studies, Female, Heterozygote, Humans, Hypertension epidemiology, Kidney metabolism, Male, Middle Aged, Molecular Sequence Data, Mutation, Prevalence, Sodium Chloride metabolism, Solute Carrier Family 12, Member 1, Solute Carrier Family 12, Member 3, Blood Pressure genetics, Hypertension genetics, Potassium Channels, Inwardly Rectifying genetics, Receptors, Drug genetics, Sodium-Potassium-Chloride Symporters genetics, Symporters genetics
Abstract

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

Published
2008
Full Text
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50. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells.

Author

Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, Tigelaar RE, and Lifton RP

Subjects
Amino Acid Sequence, Animals, Codon, Nonsense, Genetic Linkage, Haplotypes, Immunoglobulins chemistry, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Protein Conformation, Receptors, Antigen, T-Cell, gamma-delta analysis, Epidermis immunology, Immunoglobulins genetics, Immunoglobulins immunology, Multigene Family, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes immunology
Abstract

B cells, alphabeta T cells and gammadelta T cells are conserved lymphocyte subtypes encoding their antigen receptors from somatically rearranged genes. alphabeta T cells undergo positive selection in the thymus by engagement of their T cell receptors (TCRs) with self-peptides presented by major histocompatibility complex molecules. The molecules that select gammadelta T cells are unknown. Vgamma5+Vdelta1+ cells comprise 90% of mouse epidermal gammadelta T cells. By mapping and genetic complementation using a strain showing loss of Vgamma5+Vdelta1+ cells due to a failure of thymic selection, we show that this defect is caused by mutation in Skint1, a newly identified gene expressed in thymus and skin that encodes a protein with immunoglobulin-like and transmembrane domains. Skint1 is the prototypic member of a rapidly evolving family of at least 11 genes in mouse, with greatest similarity to the butyrophilin genes. These findings define a new family of proteins mediating key epithelial-immune interactions.

Published
2008
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