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1. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study

Author

Bowman P., Sulen A., Barbetti F., Beltrand J., Svalastoga P., Codner E., Tessmann E. H., Juliusson P. B., Skrivarhaug T., Pearson E. R., Flanagan S. E., Babiker T., Thomas N. J., Shepherd M. H., Ellard S., Klimes I., Szopa M., Polak M., Iafusco D., Hattersley A. T., Njolstad P. R., Aisenberg J., Akkurt I., Abdul-Latif H., Al-Abdullah A., Barak L., Van Den Bergh J., Bertrand A. -M., Bizzarri C., Bonfanti R., Bruel H., Burrows A., Cadario F., Cameron F. J., Carson D., Cartigny M., Cauvin V., Cave H., Chakera A., Chetan R., Chiari G., Couch B., Coutant R., Cummings E., Dankovcikova A., Davis L., Deiss D., Delvecchio M., Faleschini E., Fauret A. -L., Finn R., Ford T., Franco E. D., Gallen B. D., Gasperikova D., Guntamukkala P., Hakeem V., Hasegawa S., Hathout E. H., Heffernan E., Hill D., Ho J., Hoarau M., Holl R., Hoddinott R., Houghton J., Howard N., Hughes N., Hunter I., Hogasen A. K., Kuulasmaa H., Ioacara S., Iotova V., Irgens H., Jaap A., Jones K., Kapellen T., Kaufman E., Klinge A., Klupa T., Krishnaswamy R., Lafferty T., LeGault L., Lambert P., Malecki M. T., Malievsky O., Mathew R., Mathews F., McVie R., Menzel U., Metz C., Meulen J. V. D., Modgil G., Mul D., Muther S., Nuboer R., O'Connell S. M., O'Riordan S., Palko M., Patel K. A., Pesavento R., Piccinno E., Pillai J. K., Pruhova S., Punthakee Z., Rabbone I., Raile K., Rincon M., Rose D., Sanchez J., Sandereson S., Saxena V., Schebek M., Schmidt D., Shehadeh N., Shiels J. P. H., Silva J. M. C. L., Stanik J., Tinklin T., Tjora E., Tumini S., Tuomi T., Uehara A., Velde R. V. D., Vermeulen G., Visser U., Voorhoeve P., Walker J., Weill J., Weisner T., Werner A., Williams T., Woodhead H., oddegard R., Bowman, Pamela, Sulen, Åsta, Barbetti, Fabrizio, Beltrand, Jacque, Svalastoga, Pernille, Codner, Ethel, Tessmann, Ellen H, Juliusson, Petur B, Skrivarhaug, Torild, Pearson, Ewan R, Flanagan, Sarah E, Babiker, Tarig, Thomas, Nicholas J, Shepherd, Maggie H, Ellard, Sian, Klimes, Iwar, Szopa, Magdalena, Polak, Michel, Iafusco, Dario, Hattersley, Andrew T, Njølstad, Pål R, Aisenberg, Javier, Akkurt, Ilker, Abdul-Latif, Hussein, Al-Abdullah, Anee, Barak, Lubomir, Van Den Bergh, Joop, Bertrand, Anne-Marie, Bizzarri, Carla, Bonfanti, Riccardo, Bruel, Henri, Burrows, Anthony, Cadario, Francesco, Cameron, Fergus J., Carson, Denni, Cartigny, Maryse, Cauvin, Vittoria, Cave, Helene, Chakera, Ali, Chetan, Ravi, Chiari, Giovanni, Couch, Bob, Coutant, Régi, Cummings, Elizabeth, Dankovcikova, Adriana, Davis, Liz, Deiss, Dorothee, Delvecchio, Maurizio, Faleschini, Elena, Fauret, Anne-Laure, Finn, Roisin, Ford, Tamsin, Franco, Elisa De, Gallen, Bastian De, Gasperíková, Daniela, Guntamukkala, Padma, Hakeem, Vaseem, Hasegawa, Shinji, Hathout, Eba H., Heffernan, Emmeline, Hill, David, Ho, Josephine, Hoarau, Marie, Holl, Reinhard, Hoddinott, Rebecca, Houghton, Jane, Howard, Neville, Hughes, Natalie, Hunter, Ian, Høgåsen, Anne Kirsti, Kuulasmaa, Helena, Iocara, Sorin, Iotova, Violeta, Irgens, Henrik, Jaap, Alan, Jones, Kenneth, Kapellen, Thoma, Kaufman, Ellen, Klinge, Andrea, Klupa, Tomasz, Krishnaswamy, Ramaiyer, Lafferty, Tony, Legault, Laurent, Lambert, Paul, Malecki, Maciej T, Malievsky, Olag, Mathew, Revi, Mathews, France, Mcvie, Robert, Menzel, Ulrike, Metz, Chantale, Meulen, John Van Der, Modgil, Gita, Mul, Dick, Muther, Silvia, Nuboer, Roo, O'Connell, Susan M., O'Riordan, Stephen, Palko, Miroslav, Patel, Kashyap Amratlal, Pesavento, Roberta, Piccinno, Elvira, Pillai, Janani Kumaraguru, Pruhova, Stephanka, Punthakee, Zubin, Rabbone, Ivana, Raile, Klemen, Rincon, Marielisa, Rose, Danette, Sanchez, Janine, Sandereson, Susan, Saxena, Vinay, Schebek, Martin, Schmidt, Dorothee, Shehadeh, Naim, Shiels, Julian P. H., Silva, Jose M. C. L, Stanik, Juraj, Tinklin, Tracy, Tjora, Erling, Tumini, Stefano, Tuomi, Tiinamaija, Uehara, Akiko, Velde, Robert Van der, Vermeulen, Guido, Visser, Uma, Voorhoeve, Paul, Walker, Jan, Weill, Jaque, Weisner, Tobia, Werner, Andrea, Williams, Toni, Woodhead, Helen, Øddegård, Rønnaug, Bowman, P., Sulen, A., Barbetti, F., Beltrand, J., Svalastoga, P., Codner, E., Tessmann, E. H., Juliusson, P. B., Skrivarhaug, T., Pearson, E. R., Flanagan, S. E., Babiker, T., Thomas, N. J., Shepherd, M. H., Ellard, S., Klimes, I., Szopa, M., Polak, M., Iafusco, D., Hattersley, A. T., Njolstad, P. R., Aisenberg, J., Akkurt, I., Abdul-Latif, H., Al-Abdullah, A., Barak, L., Van Den Bergh, J., Bertrand, A. -M., Bizzarri, C., Bonfanti, R., Bruel, H., Burrows, A., Cadario, F., Cameron, F. J., Carson, D., Cartigny, M., Cauvin, V., Cave, H., Chakera, A., Chetan, R., Chiari, G., Couch, B., Coutant, R., Cummings, E., Dankovcikova, A., Davis, L., Deiss, D., Delvecchio, M., Faleschini, E., Fauret, A. -L., Finn, R., Ford, T., Franco, E. D., Gallen, B. D., Gasperikova, D., Guntamukkala, P., Hakeem, V., Hasegawa, S., Hathout, E. H., Heffernan, E., Hill, D., Ho, J., Hoarau, M., Holl, R., Hoddinott, R., Houghton, J., Howard, N., Hughes, N., Hunter, I., Hogasen, A. K., Kuulasmaa, H., Ioacara, S., Iotova, V., Irgens, H., Jaap, A., Jones, K., Kapellen, T., Kaufman, E., Klinge, A., Klupa, T., Krishnaswamy, R., Lafferty, T., Legault, L., Lambert, P., Malecki, M. T., Malievsky, O., Mathew, R., Mathews, F., Mcvie, R., Menzel, U., Metz, C., Meulen, J. V. D., Modgil, G., Mul, D., Muther, S., Nuboer, R., O'Connell, S. M., O'Riordan, S., Palko, M., Patel, K. A., Pesavento, R., Piccinno, E., Pillai, J. K., Pruhova, S., Punthakee, Z., Rabbone, I., Raile, K., Rincon, M., Rose, D., Sanchez, J., Sandereson, S., Saxena, V., Schebek, M., Schmidt, D., Shehadeh, N., Shiels, J. P. H., Silva, J. M. C. L., Stanik, J., Tinklin, T., Tjora, E., Tumini, S., Tuomi, T., Uehara, A., Velde, R. V. D., Vermeulen, G., Visser, U., Voorhoeve, P., Walker, J., Weill, J., Weisner, T., Werner, A., Williams, T., Woodhead, H., and Oddegard, R.

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract

Background: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients. Methods: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA 1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817. Findings: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA 1c and sulfonylurea at all time points (ie, pre-transfer [for HbA 1c ], year 1, and most recent follow-up; n=64)—median HbA 1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p

Published
2018

2. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study

Author

Bowman, P, Sulen, A, Barbetti, F, Beltrand, J, Svalastoga, P, Codner, E, Tessmann, EH, Juliusson, PB, Skrivarhaug, T, Pearson, ER, Flanagan, SE, Babiker, T, Thomas, NJ, Shepherd, MH, Ellard, S, Klimes, I, Szopa, M, Polak, M, Iafusco, D, Hattersley, AT, Njolstad, PR, Houghton, J, Patel, KA, Mathews, F, De Franco, E, Ford, T, Pillai, JK, Finn, R, Chakera, A, Iotova, V, Malecki, MT, Klupa, T, Gasperikova, D, Stanik, J, Barak, L, Dankovcikova, A, Palko, M, Walker, J, Visser, U, Howard, N, Lafferty, T, Cummings, E, Guntamukkala, P, Rose, D, Hughes, N, Couch, B, Punthakee, Z, Van der Meulen, J, LeGault, L, Sanderson, S, Krishnaswamy, R, Ho, J, Modgil, G, Lambert, P, Shield, JPH, Hoddinott, R, Burrows, A, Chetan, R, Hakeem, V, Werner, A, Muther, S, Deiss, D, Raile, K, Weisner, T, Kapellen, T, Akkurt, I, Menzel, U, Klinge, A, Schmidt, D, Heffernan, E, Carson, D, Uehara, A, Hasegawa, S, Kuulasmaa, H, Tuomi, T, Vermeulen, G, Mul, D, Jaap, A, Hill, D, Hunter, I, Rincon, M, McVie, R, Williams, T, Saxena, V, Al-Abdullah, A, Tinklin, T, Kaufman, E, Davis, L, O'Riordan, S, O'Connell, SM, Holl, R, Schebek, M, De Gallen, B, Voorhoeve, P, Malievsky, O, Mathew, R, Abdul-Latif, H, Aisenberg, J, Ioacara, S, Cameron, FJ, Sanchez, J, Jones, K, Van der Velde, R, Van den Bergh, J, Woodhead, H, Tjora, E, Irgens, H, Hogåsen, AK, Odegard, R, Hathout, EH, Nuboer, R, Pruhova, S, Shehadeh, N, Silva, JMCL, Cave, H, Fauret, A-L, Hoarau, M, Coutant, R, Metz, C, Bertrand, A-M, Bruel, H, Cartigny, M, Weill, J, Bizzarri, C, Bonfanti, R, Cadario, F, Cauvin, V, Chiari, G, Delvecchio, M, Piccinno, E, Faleschini, E, Pesavento, R, Rabbone, I, Tumini, S, Bowman, P, Sulen, A, Barbetti, F, Beltrand, J, Svalastoga, P, Codner, E, Tessmann, EH, Juliusson, PB, Skrivarhaug, T, Pearson, ER, Flanagan, SE, Babiker, T, Thomas, NJ, Shepherd, MH, Ellard, S, Klimes, I, Szopa, M, Polak, M, Iafusco, D, Hattersley, AT, Njolstad, PR, Houghton, J, Patel, KA, Mathews, F, De Franco, E, Ford, T, Pillai, JK, Finn, R, Chakera, A, Iotova, V, Malecki, MT, Klupa, T, Gasperikova, D, Stanik, J, Barak, L, Dankovcikova, A, Palko, M, Walker, J, Visser, U, Howard, N, Lafferty, T, Cummings, E, Guntamukkala, P, Rose, D, Hughes, N, Couch, B, Punthakee, Z, Van der Meulen, J, LeGault, L, Sanderson, S, Krishnaswamy, R, Ho, J, Modgil, G, Lambert, P, Shield, JPH, Hoddinott, R, Burrows, A, Chetan, R, Hakeem, V, Werner, A, Muther, S, Deiss, D, Raile, K, Weisner, T, Kapellen, T, Akkurt, I, Menzel, U, Klinge, A, Schmidt, D, Heffernan, E, Carson, D, Uehara, A, Hasegawa, S, Kuulasmaa, H, Tuomi, T, Vermeulen, G, Mul, D, Jaap, A, Hill, D, Hunter, I, Rincon, M, McVie, R, Williams, T, Saxena, V, Al-Abdullah, A, Tinklin, T, Kaufman, E, Davis, L, O'Riordan, S, O'Connell, SM, Holl, R, Schebek, M, De Gallen, B, Voorhoeve, P, Malievsky, O, Mathew, R, Abdul-Latif, H, Aisenberg, J, Ioacara, S, Cameron, FJ, Sanchez, J, Jones, K, Van der Velde, R, Van den Bergh, J, Woodhead, H, Tjora, E, Irgens, H, Hogåsen, AK, Odegard, R, Hathout, EH, Nuboer, R, Pruhova, S, Shehadeh, N, Silva, JMCL, Cave, H, Fauret, A-L, Hoarau, M, Coutant, R, Metz, C, Bertrand, A-M, Bruel, H, Cartigny, M, Weill, J, Bizzarri, C, Bonfanti, R, Cadario, F, Cauvin, V, Chiari, G, Delvecchio, M, Piccinno, E, Faleschini, E, Pesavento, R, Rabbone, I, and Tumini, S

Abstract

BACKGROUND: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients. METHODS: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817. FINDINGS: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at al

Published
2018

8. Program and abstracts for the 2011 Meeting of the Society for Glycobiology

Author

Hollingsworth, MT, Hart, GW, Paulson, JC, Stansell, E, Canis, K, Huang, IC, Panico, M, Morris, H, Haslam, S, Farzan, M, Dell, A, Desrosiers, R, von Itzstein, M, Matroscovich, M, Luther, KB, Hülsmeier, AJ, Schegg, B, Hennet, T, Nycholat, C, McBride, R, Ekiert, D, Xu, R, Peng, W, Razi, N, Gilbert, M, Wakarchuk, W, Wilson, IA, Gahlay, G, Geisler, C, Aumiller, JJ, Moremen, K, Steel, J, Labaer, J, Jarvis, DL, Drickamer, K, Taylor, M, Nizet, V, Rabinovich, G, Lewis, C, Cobb, B, Kawasaki, N, Rademacher, C, Chen, W, Vela, J, Maricic, I, Crocker, P, Kumar, V, Kronenberg, M, Paulson, J, Glenn, K, Mallinger, A, Wen, H, Srivastava, L, Tundup, S, Harn, D, Menon, AK, Yamaguchi, Y, Mkhikian, H, Grigorian, A, Li, C, Chen, HL, Newton, B, Zhou, RW, Beeton, C, Torossian, S, Tatarian, GG, Lee, SU, Lau, K, Walker, E, Siminovitch, KA, Chandy, KG, Yu, Z, Dennis, JW, Demetriou, M, Pandey, MS, Baggenstoss, BA, Washburn, JL, Weigel, PH, Chen, CI, Keusch, JJ, Klein, D, Hofsteenge, J, Gut, H, Szymanski, C, Feldman, M, Schaffer, C, Gao, Y, Strum, S, Liu, B, Schutzbach, JS, Druzhinina, TN, Utkina, NS, Torgov, VI, Szarek, WA, Wang, L, Brockhausen, I, Hitchen, P, Peyfoon, E, Meyer, B, Albers, SV, Chen, C, Newburg, DS, Jin, C, Dinglasan, RD, Beverley, SM, Guo, H, Novozhilova, N, Hickerson, S, Elnaiem, DE, Sacks, D, Turco, SJ, McKay, D, Castro, E, Takahashi, H, Straus, AH, Stalnaker, SH, Live, D, Boons, GJ, Wells, L, Stuart, R, Aoki, K, Boccuto, L, Zhang, Q, Wang, H, Bartel, F, Fan, X, Saul, R, Chaubey, A, Yang, X, Steet, R, Schwartz, C, Tiemeyer, M, Pierce, M, Kraushaar, DC, Condac, E, Nakato, H, Nishihara, S, Sasaki, N, Hirano, K, Nasirikenari, M, Collins, CC, Lau, JT, Devarapu, SK, Jeyaweerasinkam, S, Albiez, RS, Kiessling, L, Gu, J, Clark, GF, Gagneux, P, Ulm, C, Mahavadi, P, Müller, S, Rinné, S, Geyer, H, Gerardy-Schahn, R, Mühlenhoff, M, Günther, A, Geyer, R, Galuska, SP, Shibata, T, Sugihara, K, Nakayama, J, Fukuda, M, Fukuda, MN, Ishikawa, A, Terao, M, Kimura, A, Kato, A, Katayama, I, Taniguchi, N, Miyoshi, E, Aderem, A, Yoneyama, T, Angata, K, Bao, X, Chanda, S, Lowe, J, Sonon, R, Ishihara, M, Talabnin, K, Wang, Z, Black, I, Naran, R, Heiss, C, Azadi, P, Hurum, D, Rohrer, J, Balland, A, Valliere-Douglass, J, Kodama, P, Mujacic, M, Eakin, C, Brady, L, Wang, WC, Wallace, A, Treuheit, M, Reddy, P, Schuman, B, Fisher, S, Borisova, S, Coates, L, Langan, P, Evans, S, Yang, SJ, Zhang, H, Hizal, DB, Tian, Y, Sarkaria, V, Betenbaugh, M, Lütteke, T, Agravat, S, Cholleti, S, Morris, T, Saltz, J, Song, X, Cummings, R, Smith, D, Hofhine, T, Nishida, C, Mialy, R, Sophie, D, Sebastien, F, Patricia, C, Eric, S, Stephane, H, Mokros, D, Joosten, RP, Dominik, A, Vriend, G, Nguyen, LD, Martinez, J, Hinderlich, S, Reissig, HU, Reutter, W, Fan, H, Saenger, W, Moniot, S, Asada, H, Nakahara, T, Miura, Y, Stevenson, T, Yamazaki, T, De Castro, C, Burr, T, Lanzetta, R, Molinaro, A, Parrilli, M, Sule, S, Gerken, TA, Revpredo, L, Thome, J, Cardenas, G, Almeida, I, Leung, MY, Yan, S, Paschinger, K, Bleuler-Martinez, S, Jantsch, V, Wilson, I, Yoshimura, Y, Adlercreutz, D, Mannerstedt, K, Wakarchuk, WW, Dovichi, NJ, Hindsgaul, O, Palcic, MM, Chandrasekaran, A, Bharadwaj, R, Deng, K, Adams, P, Singh, A, Datta, A, Konasani, V, Imamura, A, Lowry, T, Scaman, C, Zhao, Y, Zhou, YD, Yang, K, Zhang, XL, Leymarie, N, Hartshorn, K, White, M, Cafarella, T, Seaton, B, Rynkiewicz, M, Zaia, J, Acosta-Blanco, I, Ortega-Francisco, S, Dionisio-Vicuña, M, Hernandez-Flores, M, Fuentes-Romero, L, Newburg, D, Soto-Ramirez, LE, Ruiz-Palacios, G, Viveros-Rogel, M, Tong, C, Li, W, Kong, L, Qu, M, Jin, Q, Lukyanov, P, Zhang, W, Chicalovets, I, Molchanova, V, Wu, AM, Liu, JH, Yang, WH, Nussbaum, C, Grewal, PK, Sperandio, M, Marth, JD, Yu, R, Usuki, S, Wu, HC, O'Brien, D, Piskarev, V, Ramadugu, SK, Kashyap, HK, Ghirlanda, G, Margulis, C, Brewer, C, Gomery, K, Müller-Loennies, S, Brooks, CL, Brade, L, Kosma, P, Di Padova, F, Brade, H, Evans, SV, Asakawa, K, Kawakami, K, Kushi, Y, Suzuki, Y, Nozaki, H, Itonori, S, Malik, S, Lebeer, S, Petrova, M, Balzarini, J, Vanderleyden, J, Naito-Matsui, Y, Takematsu, H, Murata, K, Kozutsumi, Y, Subedi, GP, Satoh, T, Hanashima, S, Ikeda, A, Nakada, H, Sato, R, Mizuno, M, Yuasa, N, Fujita-Yamaguchi, Y, Vlahakis, J, Nair, DG, Wang, Y, Allingham, J, Anastassiades, T, Strachan, H, Johnson, D, Orlando, R, Harenberg, J, Haji-Ghassemi, O, Mackenzie, R, Lacerda, T, Toledo, M, Straus, A, Takahashi, HK, Woodrum, B, Ruben, M, O'Keefe, B, Samli, KN, Yang, L, Woods, RJ, Jones, MB, Maxwell, J, Song, EH, Manganiello, M, Chow, YH, Convertine, AJ, Schnapp, LM, Stayton, PS, Ratner, DM, Yegorova, S, Rodriguez, MC, Minond, D, Jiménez-Barbero, J, Calle, L, Ardá, A, Gabius, HJ, André, S, Martinez-Mayorga, K, Yongye, AB, Cudic, M, Ali, MF, Chachadi, VB, Cheng, PW, Kiwamoto, T, Na, HJ, Brummet, M, Finn, MG, Hong, V, Polonskaya, Z, Bovin, NV, Hudson, S, Bochner, B, Gallogly, S, Krüger, A, Hanley, S, Gerlach, J, Hogan, M, Ward, C, Joshi, L, Griffin, M, Demarco, C, Deveny, R, Aggeler, R, Hart, C, Nyberg, T, Agnew, B, Akçay, G, Ramphal, J, Calabretta, P, Nguyen, AD, Kumar, K, Eggers, D, Terrill, R, d'Alarcao, M, Ito, Y, Vela, JL, Matsumura, F, Hoshino, H, Lee, H, Kobayashi, M, Borén, T, Jin, R, Seeberger, PH, Pitteloud, JP, Cudic, P, Von Muhlinen, N, Thurston, T, von Muhlinen, N, Wandel, M, Akutsu, M, Foeglein, AÁ, Komander, D, Randow, F, Maupin, K, Liden, D, Haab, B, Dam, TK, Brown, RK, Wiltzius, M, Jokinen, M, Andre, S, Kaltner, H, Bullen, J, Balsbaugh, J, Neumann, D, Hardie, G, Shabanowitz, J, Hunt, D, Hart, G, Mi, R, Ding, X, Van Die, I, Chapman, AB, Cummings, RD, Ju, T, Aryal, R, Ashley, J, Feng, X, Hanover, JA, Wang, P, Keembiyehetty, C, Ghosh, S, Bond, M, Krause, M, Love, D, Radhakrishnan, P, Grandgenet, PM, Mohr, AM, Bunt, SK, Yu, F, Hollingsworth, MA, Ethen, C, Machacek, M, Prather, B, Wu, Z, Kotu, V, Zhao, P, Zhang, D, van der Wel, H, Johnson, JM, West, CM, Abdulkhalek, S, Amith, SR, Jayanth, P, Guo, M, Szewczuk, M, Ohtsubo, K, Chen, M, Olefsky, J, Marth, J, Zapater, J, Foley, D, Colley, K, Kawashima, N, Fujitani, N, Tsuji, D, Itoh, K, Shinohara, Y, Nakayama, K, Zhang, L, Ten Hagen, K, Koren, S, Yehezkel, G, Cohen, L, Kliger, A, Khalaila, I, Finkelstein, E, Parker, R, Kohler, J, Sacoman, J, Badish, L, Hollingsworth, R, Tian, E, Hoffman, M, Hou, X, Tashima, Y, Stanley, P, Kizuka, Y, Kitazume, S, Yoshida, M, Kunze, A, Nasir, W, Bally, M, Hook, F, Larson, G, Mahan, A, Alter, G, Zeidan, Q, Copeland, R, Pokrovskaya, I, Willett, R, Smith, R, Morelle, W, Kudlyk, T, Lupashin, V, Vasudevan, D, Takeuchi, H, Majerus, E, Haltiwanger, RS, Boufala, S, Lee, YA, Min, D, Kim, SH, Shin, MH, Gesteira, T, Pol-Fachin, L, Coulson-Thomas, VJ, Verli, H, Nader, H, Liu, X, Yang, P, Thoden, J, Holden, H, Tytgat, H, Sánchez-Rodríguez, A, Schoofs, G, Verhoeven, T, De Keersmaecker, S, Marchal, K, Ventura, V, Sarah, N, Joann, P, Ding, Y, Jarrell, K, Cook, MC, Gibeault, S, Filippenko, V, Ye, Q, Wang, J, Kunkel, JP, Arteaga-Cabello, FJ, Arciniega-Fuentes, MT, McCoy, J, Ruiz-Palacios, GM, Francoleon, D, Loo, RO, Loo, J, Ytterberg, AJ, Kim, U, Gunsalus, R, Costello, C, Soares, R, Assis, R, Ibraim, I, Noronha, F, De Godoy, AP, Bale, MS, Xu, Y, Brown, K, Blader, I, West, C, Chen, S, Ye, X, Xue, C, Li, G, Yu, G, Yin, L, Chai, W, Gutierrez-Magdaleno, G, Tan, C, Wu, D, Li, Q, Hu, H, Ye, M, Liu, D, Mink, W, Kaese, P, Fujiwara, M, Uchimura, K, Sakai, Y, Nakada, T, Mabashi-Asazuma, H, Toth, AM, Scott, DW, Chacko, BK, Patel, RP, Batista, F, Mercer, N, Ramakrishnan, B, Pasek, M, Boeggeman, E, Verdi, L, Qasba, PK, Tran, D, Lim, JM, Liu, M, Mo, KF, Kirby, P, Yu, X, Lin, C, Costello, CE, Akama, TO, Nakamura, T, Huang, Y, Shi, X, Han, L, Yu, SH, Zhang, Z, Knappe, S, Till, S, Nadia, I, Catarello, J, Quinn, C, Julia, N, Ray, J, Tran, T, Scheiflinger, F, Szabo, C, Dockal, M, Niimi, S, Hosono, T, Michikawa, M, Kannagi, R, Takashima, S, Amano, J, Nakamura, N, Kaneda, E, Nakayama, Y, Kurosaka, A, Takada, W, Matsushita, T, Hinou, H, Nishimura, S, Igarashi, K, Abe, H, Mothere, M, Leonhard-Melief, C, Johnson, H, Nagy, T, Nairn, A, Rosa, MD, Porterfield, M, Kulik, M, Dalton, S, Pierce, JM, Hansen, SF, McAndrew, R, Degiovanni, A, McInerney, P, Pereira, JH, Hadi, M, Scheller, HV, Barb, A, Prestegard, J, Zhang, S, Jiang, J, Tharmalingam, T, Pluta, K, McGettigan, P, Gough, R, Struwe, W, Fitzpatrick, E, Gallagher, ME, Rudd, PM, Karlsson, NG, Carrington, SD, Katoh, T, Panin, V, Gelfenbeyn, K, Freire-de-Lima, L, Handa, K, Hakomori, SI, Bielik, AM, McLeod, E, Landry, D, Mendoza, V, Guthrie, EP, Mao, Y, Wang, X, Moremen, KW, Meng, L, Ramiah, AP, Gao, Z, Johnson, R, Xiang, Y, Rosa, MDEL, Wu, SC, Gilbert, HJ, Karaveg, K, Chen, L, Wang, BC, Mast, S, Sun, B, Fulton, S, Kimzey, M, Pourkaveh, S, Minalla, A, Haxo, T, Wegstein, J, Murray, AK, Nichols, RL, Giannini, S, Grozovsky, R, Begonja, AJ, Hoffmeister, KM, Suzuki-Anekoji, M, Suzuki, A, Yu, SY, Khoo, KH, van Alphen, L, Fodor, C, Wenzel, C, Ashmus, R, Miller, W, Stahl, M, Stintzi, A, Lowary, T, Wiederschain, G, Saba, J, Zumwalt, A, Meitei, NS, Apte, A, Viner, R, Gandy, M, Debowski, A, Stubbs, K, Witzenman, H, Pandey, D, Repnikova, E, Nakamura, M, Islam, R, Kc, N, Caster, C, Chaubard, JL, Krishnamurthy, C, Hsieh-Wilson, L, Pranskevich, J, Rangarajan, J, Guttman, A, Szabo, Z, Karger, B, Chapman, J, Chavaroche, A, Bionda, N, Fields, G, Jacob, F, Tse, BW, Guertler, R, Nixdorf, S, Hacker, NF, Heinzelmann-Schwarz, V, Yang, F, Kohler, JJ, Losfeld, ME, Ng, B, Freeze, HH, He, P, Wondimu, A, Liu, Y, Zhang, Y, Su, Y, Ladisch, S, Grewal, P, Mann, C, Ditto, D, Lardone, R, Le, D, Varki, N, Kulinich, A, Kostjuk, O, Maslak, G, Pismenetskaya, I, Shevtsova, A, Takeishi, S, Okudo, K, Moriwaki, K, Terao, N, Kamada, Y, Kuroda, S, Li, Y, Peiris, D, Markiv, A, Dwek, M, Adamczyk, B, Thanabalasingham, G, Huffman, J, Kattla, J, Novokmet, M, Rudan, I, Gloyn, A, Hayward, C, Reynolds, R, Hansen, T, Klimes, I, Njolstad, P, Wilson, J, Hastie, N, Campbell, H, McCarthy, M, Rudd, P, Owen, K, Lauc, G, Wright, A, Goletz, S, Stahn, R, Danielczyk, A, Baumeister, H, Hillemann, A, Löffler, A, Stöckl, L, Jahn, D, Bahrke, S, Flechner, A, Schlangstedt, M, Karsten, U, Goletz, C, Mikolajczyk, S, Ulsemer, P, Gao, N, Cline, A, Flanagan-Steet, H, Sadler, KC, Lehrman, MA, Coulson-Thomas, YM, Gesteira, TF, Mader, AM, Waisberg, J, Pinhal, MA, Friedl, A, Toma, L, Nader, HB, Mbua, EN, Johnson, S, Wolfert, M, Dimitrievska, S, Huizing, M, Niklason, L, Perdivara, I, Petrovich, R, Tokar, EJ, Waalkes, M, Fraser, P, Tomer, K, Chu, J, Rosa, S, Mir, A, Lehrman, M, Sadler, K, Lauer, M, Hascall, V, Calabro, A, Cheng, G, Swaidani, S, Abaddi, A, Aronica, M, Yuzwa, S, Shan, X, Macauley, M, Clark, T, Skorobogatko, Y, Vosseller, K, Vocadlo, D, Banerjee, A, Baksi, K, Banerjee, D, Melcher, R, Kraus, I, Moeller, D, Demmig, S, Rogoll, D, Kudlich, T, Scheppach, W, Scheurlen, M, Hasilik, A, Steirer, L, Lee, J, Moe, G, Troy, FA, Wang, F, Xia, B, Wang, B, Yi, S, Yu, H, Suzuki, M, Kobayashi, T, Sato, Y, Zhou, H, Briscoe, A, Lee, R, Wolfert, MA, Matsumoto, Y, Hamamura, K, Yoshida, T, Akita, K, Okajima, T, Furukawa, K, Urano, T, Ruhaak, LR, Miyamoto, S, and Lebrilla, CB

Subjects
Embryogenesis, Cancer screening, Cancer research, medicine, Cell migration, Neural cell adhesion molecule, Biology, medicine.disease, Biochemistry, Metastasis
Abstract

Cell surface mucins configure the cell surface by presenting extended protein backbones that are heavily O-glycosylated. The glycopeptide structures establish physicochemical properties at the cell surface that enable and block the formation of biologically important molecular complexes. Some mucins, such as MUC1, associate with receptor tyrosine kinases and other cell surface receptors, and engage in signal transduction in order to communicate information regarding conditions at the cell surface to the nucleus. In that context, the MUC1 cytoplasmic tail (MUC1CT) receives phosphorylation signals from receptor tyrosine kinases and serine/threonine kinases, which enables its association with different signaling complexes that conduct these signals to the nucleus and perhaps other subcellular organelles. We have detected the MUC1CT at promoters of over 500 genes, in association with several different transcription factors, and have shown that promoter occupancy can vary under different growth factor conditions. However, the full biochemical nature of the nuclear forms of MUC1 and its function at these promoter regions remain undefined. I will present evidence that nuclear forms of the MUC1CT include extracellular and cytoplasmic tail domains. In addition, I will discuss evidence for a hypothesis that the MUC1CT possesses a novel catalytic function that enables remodeling of the transcription factor occupancy of promoters, and thereby engages in regulation of gene expression.

Published
2016

12. Melanocortin-4 Receptor Gene Mutations in Obese Slovak Children

Author

STANIKOVA, D., primary, SUROVA, M., additional, TICHA, L., additional, PETRASOVA, M., additional, VIRGOVA, D., additional, HUCKOVA, M., additional, SKOPKOVA, M., additional, LOBOTKOVA, D., additional, VALENTINOVA, L., additional, MOKAN, M., additional, STANIK, J., additional, KLIMES, I., additional, and GASPERIKOVA, D., additional

Published
2015
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15. Age of obesity onset in MC4R mutation carriers

Author

Stanikova, D., primary, Surova, M., additional, Buzga, M., additional, Skopkova, M., additional, Ticha, L., additional, Petrasova, M., additional, Huckova, M., additional, Gabcova-Balaziova, D., additional, Valentova, L., additional, Mokan, M., additional, Zavacka, I., additional, Stanik, J., additional, Klimes, I., additional, and Gasperikova, D., additional

Published
2015
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16. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.

Author

Bowman P, Sulen Å, Barbetti F, Beltrand J, Svalastoga P, Codner E, Tessmann EH, Juliusson PB, Skrivarhaug T, Pearson ER, Flanagan SE, Babiker T, Thomas NJ, Shepherd MH, Ellard S, Klimes I, Szopa M, Polak M, Iafusco D, Hattersley AT, and Njølstad PR

Subjects
Adolescent, Adult, Biomarkers analysis, Blood Glucose analysis, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus genetics, Diabetes Mellitus pathology, Female, Follow-Up Studies, Glycated Hemoglobin analysis, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases genetics, Infant, Newborn, Diseases pathology, Male, Mutation, Prognosis, Young Adult, Diabetes Mellitus drug therapy, Hypoglycemic Agents therapeutic use, Infant, Newborn, Diseases drug therapy, Potassium Channels, Inwardly Rectifying genetics, Sulfonylurea Compounds therapeutic use
Abstract

Background: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients., Methods: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA 1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817., Findings: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA 1c and sulfonylurea at all time points (ie, pre-transfer [for HbA 1c ], year 1, and most recent follow-up; n=64)-median HbA 1c was 8·1% (IQR 7·2-9·2; 65·0 mmol/mol [55·2-77·1]) before transfer to sulfonylureas, 5·9% (5·4-6·5; 41·0 mmol/mol [35·5-47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9-7·3; 46·4 mmol/mol [41·0-56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2-10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14-0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12-0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5-24·0] vs 4·1 years [1·3-10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients., Interpretation: High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years., Funding: Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Published
2018
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17. DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene.

Author

Kolnikova M, Skopkova M, Ilencikova D, Foltan T, Payerova J, Danis D, Klimes I, Stanik J, and Gasperikova D

Subjects
Brain diagnostic imaging, Brain growth & development, Brain physiopathology, Brain Diseases diagnostic imaging, Brain Diseases physiopathology, Child, Preschool, Female, Humans, Phenotype, Brain Diseases genetics, Dynamin I genetics, Mutagenesis, Insertional
Published
2018
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18. Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents.

Author

Stanikova D, Buzga M, Krumpolec P, Skopkova M, Surova M, Ukropcova B, Ticha L, Petrasova M, Gabcova D, Huckova M, Piskorova L, Bozensky J, Mokan M, Ukropec J, Zavacka I, Klimes I, Stanik J, and Gasperikova D

Subjects
Adolescent, Age of Onset, Calorimetry, Indirect, Case-Control Studies, Child, Child, Preschool, Czech Republic ethnology, Female, Food Preferences, Genetic Carrier Screening, Humans, Male, Mutation, Obesity ethnology, Pedigree, Phenotype, Receptor, Melanocortin, Type 4 genetics, Severity of Illness Index, Slovakia ethnology, Basic Helix-Loop-Helix Transcription Factors genetics, Obesity genetics, Repressor Proteins genetics
Abstract

Background: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations., Methods: The SIM1 promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2-18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 MC4R variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender., Results: Seven previously described SIM1 variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 in silico software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m2; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (p = 0.02) and low fat, low carbohydrate, high protein (p = 0.02) foods compared to the obese controls., Conclusions: We have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.

Published
2017
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19. Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation.

Author

Stanik J, Skopkova M, Brennerova K, Danis D, Rosolankova M, Salingova A, Bzduch V, Klimes I, and Gasperikova D

Subjects
Adult, Child, Female, Genotype, Heterozygote, Humans, Male, Mutation, Phenotype, Congenital Hyperinsulinism genetics, Glycogen Storage Disease genetics, Hepatocyte Nuclear Factor 4 genetics
Abstract

Aim: Congenital hyperinsulinism (CHI) and glycogen storage disease (glycogenosis) are both causing hypoglycemia during infancy, but with different additional clinical features and therapeutic approach. We aimed to identify a genetic cause in a child with an ambiguous phenotype., Methods and Results: We present a child with hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in erythrocytes, increased liver transaminases, and increased echogenicity on liver ultrasonography. As both parents of the proband were referred as healthy, we raised a clinical suspicion on glycogenosis with recessive inheritance. However, whole exome sequencing revealed no mutation in genes causing glycogenosis, but a novel heterozygous variant LRG&#95;483t1: c.427-1G>A in the HNF4A gene was identified. Aberrant splicing resulting in in-frame deletion c.429&#95;476del, p.(T144&#95;I159del) was confirmed by sequencing of HNF4A transcripts reverse-transcribed from whole blood RNA. The same variant was found in five of eight tested family relatives (one of them already had diabetes, two had prediabetes). With regard to the results of DNA analysis, we added diazoxide to the therapy. Consequently, the frequency and severity of hypoglycemia in the proband decreased. We have also recommended sulfonylurea treatment after diabetes onset in adult mutation carriers., Conclusions: We have identified a novel HNF4A gene mutation in our patient with CHI and glycogenosis-like phenotype. The proband and her family members benefited from the genetic testing by WES method and consequently personalized therapy. Nevertheless, the HNF4A gene testing may be considered in selected CHI cases with glycogenosis-like phenotype prior WES analysis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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20. EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

Author

Skopkova M, Hennig F, Shin BS, Turner CE, Stanikova D, Brennerova K, Stanik J, Fischer U, Henden L, Müller U, Steinberger D, Leshinsky-Silver E, Bottani A, Kurdiova T, Ukropec J, Nyitrayova O, Kolnikova M, Klimes I, Borck G, Bahlo M, Haas SA, Kim JR, Lotspeich-Cole LE, Gasperikova D, Dever TE, and Kalscheuer VM

Subjects
Amino Acid Sequence, Family Health, Female, Genitalia abnormalities, Humans, Male, Mental Retardation, X-Linked pathology, Obesity, Pedigree, Sequence Analysis, DNA methods, Sequence Homology, Amino Acid, Syndrome, Epilepsy, Eukaryotic Initiation Factor-2 genetics, Hypogonadism, Intellectual Disability genetics, Mental Retardation, X-Linked genetics, Microcephaly, Mutation
Abstract

Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms., (© 2017 WILEY PERIODICALS, INC.)

Published
2017
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21. Genetic testing of familial hypercholesterolemia in a real clinical setting.

Author

Vohnout B, Gabcova D, Huckova M, Klimes I, Gasperikova D, and Raslova K

Subjects
Adult, Female, Genetic Markers genetics, Humans, Middle Aged, Apolipoproteins B genetics, Genetic Testing methods, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II genetics, Proprotein Convertase 9 genetics, Receptors, LDL genetics
Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by strikingly elevated low-density lipoprotein (LDL) cholesterol levels and premature atherosclerosis. For individuals with a definite or probable diagnosis of FH, molecular genetic testing is recommended. This can be justified in countries where genetic testing is broadly available and covered. On the other hand, in countries with limited access to genetic testing, it can be argued whether it is necessary and cost-effective to perform genetic testing in patients with a proven clinical diagnosis of FH. This article presents a family with FH where different family members manifested different phenotypes and discusses situations where genetic diagnosis can crucially help physicians in clinical decision-making on how to approach and treat patients.

Published
2016
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22. Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa.

Author

Skopkova M, Ciljakova M, Havlicekova Z, Vojtkova J, Valentinova L, Danis D, Murgas D, Szepeova R, Stanik J, Banovcin P, Klimes I, and Gasperikova D

Subjects
Child, Child, Preschool, Diabetes Mellitus etiology, Diabetes Mellitus pathology, Female, Gallbladder Diseases etiology, Gallbladder Diseases pathology, Gastric Mucosa surgery, Heterozygote, Humans, Intestinal Atresia etiology, Intestinal Atresia pathology, Intestine, Small abnormalities, Intestine, Small surgery, Malabsorption Syndromes genetics, Pregnancy, Regulatory Factor X Transcription Factors metabolism, Siblings, Diabetes Mellitus genetics, Gallbladder Diseases genetics, Gastric Mucosa pathology, Intestinal Atresia genetics, Regulatory Factor X Transcription Factors genetics
Abstract

Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316&#95;1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Published
2016
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23. Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss.

Author

Nayak G, Varga L, Trincot C, Shahzad M, Friedman PL, Klimes I, Greinwald JH Jr, Riazuddin SA, Masindova I, Profant M, Khan SN, Friedman TB, Ahmed ZM, Gasperikova D, Riazuddin S, and Riazuddin S

Subjects
Adolescent, Animals, Cells, Cultured, Child, Connexin 26, Connexins, DNA Mutational Analysis, Dogs, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Slovakia, Hearing Loss, Sensorineural genetics, MARVEL Domain Containing 2 Protein genetics
Abstract

Pathogenic mutations of MARVELD2, encoding tricellulin, a tricelluar tight junction protein, cause autosomal recessive non-syndromic hearing loss (DFNB49) in families of Pakistan and Czech Roma origin. In fact, they are a significant cause of prelingual hearing loss in the Czech Roma, second only to GJB2 variants. Previously, we reported that mice homozygous for p.Arg497* variant of Marveld2 had a broad phenotypic spectrum, where defects were observed in the inner ear, heart, mandibular salivary gland, thyroid gland and olfactory epithelium. The current study describes the types and frequencies of MARVELD2 alleles and clinically reexamines members of DFNB49 families. We found that MARVELD2 variants are responsible for about 1.5 % (95 % CI 0.8-2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. In addition, we identified a novel large deletion in a single family, which appears to have resulted from non-allelic homologous recombination between two similar Alu short interspersed elements. Finally, we observed no other clinical manifestations co-segregating with hearing loss in DFNB49 human families, and hypothesize that the additional abnormalities in the Marveld2 mutant mouse indicates a critical non-redundant function for tricellulin in other organ systems.

Published
2015
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24. Adipokine zinc-α2-glycoprotein regulated by growth hormone and linked to insulin sensitivity.

Author

Balaz M, Ukropcova B, Kurdiova T, Gajdosechova L, Vlcek M, Janakova Z, Fedeles J, Pura M, Gasperikova D, Smith SR, Tkacova R, Klimes I, Payer J, Wolfrum C, and Ukropec J

Subjects
Adipocytes drug effects, Adipocytes metabolism, Adipose Tissue metabolism, Administration, Oral, Adult, Aged, Case-Control Studies, Cohort Studies, Dietary Supplements, Female, Human Growth Hormone deficiency, Human Growth Hormone pharmacology, Humans, Lipid Metabolism, Male, Middle Aged, Zn-Alpha-2-Glycoprotein, Adipose Tissue drug effects, Human Growth Hormone administration & dosage, Obesity metabolism, Seminal Plasma Proteins metabolism
Abstract

Objective: Hypertrophic obesity is associated with impaired insulin sensitivity and lipid-mobilizing activity of zinc-α2-glycoprotein. Adipose tissue (AT) of growth hormone (GH) -deficient patients is characterized by extreme adipocyte hypertrophy due to defects in AT lipid metabolism. It was hypothesized that zinc-α2-glycoprotein is regulated by GH and mediates some of its beneficial effects in AT., Methods: AT from patients with GH deficiency and individuals with obesity-related GH deficit was obtained before and after 5-year and 24-month GH supplementation therapy. GH action was tested in primary human adipocytes. Relationships of GH and zinc-α2-glycoprotein with adipocyte size and insulin sensitivity were evaluated in nondiabetic patients with noncancerous cachexia and hypertrophic obesity., Results: AT in GH-deficient adults displayed a substantial reduction of zinc-α2-glycoprotein. GH therapy normalized AT zinc-α2-glycoprotein. Obesity-related relative GH deficit was associated with almost 80% reduction of zinc-α2-glycoprotein mRNA in AT. GH increased zinc-α2-glycoprotein mRNA in both AT of obese men and primary human adipocytes. Interdependence of GH and zinc-α2-glycoprotein in regulating AT morphology and metabolic phenotype was evident from their relationship with adipocyte size and AT-specific and whole-body insulin sensitivity., Conclusions: The results demonstrate that GH is involved in regulation of AT zinc-α2-glycoprotein; however, the molecular mechanism linking GH and zinc-α2-glycoprotein in AT is yet unknown., (© 2014 The Obesity Society.)

Published
2015
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