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4. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Author

Wagnon, J.L., Barker, B.S., Hounshell, J.A., Haaxma, C.A., Shealy, A., Moss, T., Parikh, S., Messer, R.D., Patel, M.K., Meisler, M.H., Wagnon, J.L., Barker, B.S., Hounshell, J.A., Haaxma, C.A., Shealy, A., Moss, T., Parikh, S., Messer, R.D., Patel, M.K., and Meisler, M.H.

Abstract

Contains fulltext : 168024.pdf (publisher's version ) (Open Access), OBJECTIVE: The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties. METHODS: Clinical exome sequencing was carried out on patients with early-onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G-protein subunit Gbetagamma, and sodium channel subunit beta1 were assessed by coimmunoprecipitation. RESULTS: We identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady-state inactivation. Protein interactions were not affected. INTERPRETATION: Recurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain-of-function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss-of-function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene- and mutation-specific treatments.

Published
2016

5. Guidelines for the use and interpretation of assays for monitoring autophagy

Author

Klionsky, D.J. Abdalla, F.C. Abeliovich, H. Abraham, R.T. Acevedo-Arozena, A. Adeli, K. Agholme, L. Agnello, M. Agostinis, P. Aguirre-Ghiso, J.A. Ahn, H.J. Ait-Mohamed, O. Ait-Si-Ali, S. Akematsu, T. Akira, S. Al-Younes, H.M. Al-Zeer, M.A. Albert, M.L. Albin, R.L. Alegre-Abarrategui, J. Aleo, M.F. Alirezaei, M. Almasan, A. Almonte-Becerril, M. Amano, A. Amaravadi, R. Amarnath, S. Amer, A.O. Andrieu-Abadie, N. Anantharam, V. Ann, D.K. Anoopkumar-Dukie, S. Aoki, H. Apostolova, N. Arancia, G. Aris, J.P. Asanuma, K. Asare, N.Y.O. Ashida, H. Askanas, V. Askew, D.S. Auberger, P. Baba, M. Backues, S.K. Baehrecke, E.H. Bahr, B.A. Bai, X.-Y. Bailly, Y. Baiocchi, R. Baldini, G. Balduini, W. Ballabio, A. Bamber, B.A. Bampton, E.T.W. Bánhegyi, G. Bartholomew, C.R. Bassham, D.C. Bast Jr., R.C. Batoko, H. Bay, B.-H. Beau, I. Béchet, D.M. Begley, T.J. Behl, C. Behrends, C. Bekri, S. Bellaire, B. Bendall, L.J. Benetti, L. Berliocchi, L. Bernardi, H. Bernassola, F. Besteiro, S. Bhatia-Kissova, I. Bi, X. Biard-Piechaczyk, M. Blum, J.S. Boise, L.H. Bonaldo, P. Boone, D.L. Bornhauser, B.C. Bortoluci, K.R. Bossis, I. Bost, F. Bourquin, J.-P. Boya, P. Boyer-Guittaut, M. Bozhkov, P.V. Brady, N.R. Brancolini, C. Brech, A. Brenman, J.E. Brennand, A. Bresnick, E.H. Brest, P. Bridges, D. Bristol, M.L. Brookes, P.S. Brown, E.J. Brumell, J.H. Brunetti-Pierri, N. Brunk, U.T. Bulman, D.E. Bultman, S.J. Bultynck, G. Burbulla, L.F. Bursch, W. Butchar, J.P. Buzgariu, W. Bydlowski, S.P. Cadwell, K. Cahová, M. Cai, D. Cai, J. Cai, Q. Calabretta, B. Calvo-Garrido, J. Camougrand, N. Campanella, M. Campos-Salinas, J. Candi, E. Cao, L. Caplan, A.B. Carding, S.R. Cardoso, S.M. Carew, J.S. Carlin, C.R. Carmignac, V. Carneiro, L.A.M. Carra, S. Caruso, R.A. Casari, G. Casas, C. Castino, R. Cebollero, E. Cecconi, F. Celli, J. Chaachouay, H. Chae, H.-J. Chai, C.-Y. Chan, D.C. Chan, E.Y. Chang, R.C.-C. Che, C.-M. Chen, C.-C. Chen, G.-C. Chen, G.-Q. Chen, M. Chen, Q. Chen, S.S.-L. Chen, W. Chen, X. Chen, X. Chen, X. Chen, Y.-G. Chen, Y. Chen, Y. Chen, Y.-J. Chen, Z. Cheng, A. Cheng, C.H.K. Cheng, Y. Cheong, H. Cheong, J.-H. Cherry, S. Chess-Williams, R. Cheung, Z.H. Chevet, E. Chiang, H.-L. Chiarelli, R. Chiba, T. Chin, L.-S. Chiou, S.-H. Chisari, F.V. Cho, C.H. Cho, D.-H. Choi, A.M.K. Choi, D. Choi, K.S. Choi, M.E. Chouaib, S. Choubey, D. Choubey, V. Chu, C.T. Chuang, T.-H. Chueh, S.-H. Chun, T. Chwae, Y.-J. Chye, M.-L. Ciarcia, R. Ciriolo, M.R. Clague, M.J. Clark, R.S.B. Clarke, P.G.H. Clarke, R. Codogno, P. Coller, H.A. Colombo, M.I. Comincini, S. Condello, M. Condorelli, F. Cookson, M.R. Coombs, G.H. Coppens, I. Corbalan, R. Cossart, P. Costelli, P. Costes, S. Coto-Montes, A. Couve, E. Coxon, F.P. Cregg, J.M. Crespo, J.L. Cronjé, M.J. Cuervo, A.M. Cullen, J.J. Czaja, M.J. D'Amelio, M. Darfeuille-Michaud, A. Davids, L.M. Davies, F.E. De Felici, M. De Groot, J.F. De Haan, C.A.M. De Martino, L. De Milito, A. De Tata, V. Debnath, J. Degterev, A. Dehay, B. Delbridge, L.M.D. Demarchi, F. Deng, Y.Z. Dengjel, J. Dent, P. Denton, D. Deretic, V. Desai, S.D. Devenish, R.J. Di Gioacchino, M. Di Paolo, G. Di Pietro, C. Díaz-Araya, G. Díaz-Laviada, I. Diaz-Meco, M.T. Diaz-Nido, J. Dikic, I. Dinesh-Kumar, S.P. Ding, W.-X. Distelhorst, C.W. Diwan, A. Djavaheri-Mergny, M. Dokudovskaya, S. Dong, Z. Dorsey, F.C. Dosenko, V. Dowling, J.J. Doxsey, S. Dreux, M. Drew, M.E. Duan, Q. Duchosal, M.A. Duff, K. Dugail, I. Durbeej, M. Duszenko, M. Edelstein, C.L. Edinger, A.L. Egea, G. Eichinger, L. Eissa, N.T. Ekmekcioglu, S. El-Deiry, W.S. Elazar, Z. Elgendy, M. Ellerby, L.M. Er Eng, K. Engelbrecht, A.-M. Engelender, S. Erenpreisa, J. Escalante, R. Esclatine, A. Eskelinen, E.-L. Espert, L. Espina, V. Fan, H. Fan, J. Fan, Q.-W. Fan, Z. Fang, S. Fang, Y. Fanto, M. Fanzani, A. Farkas, T. Farré, J.-C. Faure, M. Fechheimer, M. Feng, C.G. Feng, J. Feng, Q. Feng, Y. Fésüs, L. Feuer, R. Figueiredo-Pereira, M.E. Fimia, G.M. Fingar, D.C. Finkbeiner, S. Finkel, T. Finley, K.D. Fiorito, F. Fisher, E.A. Fisher, P.B. Flajolet, M. Florez-McClure, M.L. Florio, S. Fon, E.A. Fornai, F. Fortunato, F. Fotedar, R. Fowler, D.H. Fox, H.S. Franco, R. Frankel, L.B. Fransen, M. Fuentes, J.M. Fueyo, J. Fujii, J. Fujisaki, K. Fujita, E. Fukuda, M. Furukawa, R.H. Gaestel, M. Gailly, P. Gajewska, M. Galliot, B. Galy, V. Ganesh, S. Ganetzky, B. Ganley, I.G. Gao, F.-B. Gao, G.F. Gao, J. Garcia, L. Garcia-Manero, G. Garcia-Marcos, M. Garmyn, M. Gartel, A.L. Gatti, E. Gautel, M. Gawriluk, T.R. Gegg, M.E. Geng, J. Germain, M. Gestwicki, J.E. Gewirtz, D.A. Ghavami, S. Ghosh, P. Giammarioli, A.M. Giatromanolaki, A.N. Gibson, S.B. Gilkerson, R.W. Ginger, M.L. Ginsberg, H.N. Golab, J. Goligorsky, M.S. Golstein, P. Gomez-Manzano, C. Goncu, E. Gongora, C. Gonzalez, C.D. Gonzalez, R. González-Estévez, C. González-Polo, R.A. Gonzalez-Rey, E. Gorbunov, N.V. Gorski, S. Goruppi, S. Gottlieb, R.A. Gozuacik, D. Granato, G.E. Grant, G.D. Green, K.N. Gregorc, A. Gros, F. Grose, C. Grunt, T.W. Gual, P. Guan, J.-L. Guan, K.-L. Guichard, S.M. Gukovskaya, A.S. Gukovsky, I. Gunst, J. Gustafsson, A.B. Halayko, A.J. Hale, A.N. Halonen, S.K. Hamasaki, M. Han, F. Han, T. Hancock, M.K. Hansen, M. Harada, H. Harada, M. Hardt, S.E. Harper, J.W. Harris, A.L. Harris, J. Harris, S.D. Hashimoto, M. Haspel, J.A. Hayashi, S.-I. Hazelhurst, L.A. He, C. He, Y.-W. Hébert, M.-J. Heidenreich, K.A. Helfrich, M.H. Helgason, G.V. Henske, E.P. Herman, B. Herman, P.K. Hetz, C. Hilfiker, S. Hill, J.A. Hocking, L.J. Hofman, P. Hofmann, T.G. Höhfeld, J. Holyoake, T.L. Hong, M.-H. Hood, D.A. Hotamisligil, G.S. Houwerzijl, E.J. Høyer-Hansen, M. Hu, B. Hu, C.-A.A. Hu, H.-M. Hua, Y. Huang, C. Huang, J. Huang, S. Huang, W.-P. Huber, T.B. Huh, W.-K. Hung, T.-H. Hupp, T.R. Hur, G.M. Hurley, J.B. Hussain, S.N.A. Hussey, P.J. Hwang, J.J. Hwang, S. Ichihara, A. Ilkhanizadeh, S. Inoki, K. Into, T. Iovane, V. Iovanna, J.L. Ip, N.Y. Isaka, Y. Ishida, H. Isidoro, C. Isobe, K.-I. Iwasaki, A. Izquierdo, M. Izumi, Y. Jaakkola, P.M. Jäättelä, M. Jackson, G.R. Jackson, W.T. Janji, B. Jendrach, M. Jeon, J.-H. Jeung, E.-B. Jiang, H. Jiang, H. Jiang, J.X. Jiang, M. Jiang, Q. Jiang, X. Jiménez, A. Jin, M. Jin, S. Joe, C.O. Johansen, T. Johnson, D.E. Johnson, G.V.W. Jones, N.L. Joseph, B. Joseph, S.K. Joubert, A.M. Juhász, G. Juillerat-Jeanneret, L. Jung, C.H. Jung, Y.-K. Kaarniranta, K. Kaasik, A. Kabuta, T. Kadowaki, M. Kagedal, K. Kamada, Y. Kaminskyy, V.O. Kampinga, H.H. Kanamori, H. Kang, C. Kang, K.B. Il Kang, K. Kang, R. Kang, Y.-A. Kanki, T. Kanneganti, T.-D. Kanno, H. Kanthasamy, A.G. Kanthasamy, A. Karantza, V. Kaushal, G.P. Kaushik, S. Kawazoe, Y. Ke, P.-Y. Kehrl, J.H. Kelekar, A. Kerkhoff, C. Kessel, D.H. Khalil, H. Kiel, J.A.K.W. Kiger, A.A. Kihara, A. Kim, D.R. Kim, D.-H. Kim, D.-H. Kim, E.-K. Kim, H.-R. Kim, J.-S. Kim, J.H. Kim, J.C. Kim, J.K. Kim, P.K. Kim, S.W. Kim, Y.-S. Kim, Y. Kimchi, A. Kimmelman, A.C. King, J.S. Kinsella, T.J. Kirkin, V. Kirshenbaum, L.A. Kitamoto, K. Kitazato, K. Klein, L. Klimecki, W.T. Klucken, J. Knecht, E. Ko, B.C.B. Koch, J.C. Koga, H. Koh, J.-Y. Koh, Y.H. Koike, M. Komatsu, M. Kominami, E. Kong, H.J. Kong, W.-J. Korolchuk, V.I. Kotake, Y. Koukourakis, M.I. Kouri Flores, J.B. Kovács, A.L. Kraft, C. Krainc, D. Krämer, H. Kretz-Remy, C. Krichevsky, A.M. Kroemer, G. Krüger, R. Krut, O. Ktistakis, N.T. Kuan, C.-Y. Kucharczyk, R. Kumar, A. Kumar, R. Kumar, S. Kundu, M. Kung, H.-J. Kurz, T. Kwon, H.J. La Spada, A.R. Lafont, F. Lamark, T. Landry, J. Lane, J.D. Lapaquette, P. Laporte, J.F. László, L. Lavandero, S. Lavoie, J.N. Layfield, R. Lazo, P.A. Le, W. Le Cam, L. Ledbetter, D.J. Lee, A.J.X. Lee, B.-W. Lee, G.M. Lee, J. Lee, J.-H. Lee, M. Lee, M.-S. Lee, S.H. Leeuwenburgh, C. Legembre, P. Legouis, R. Lehmann, M. Lei, H.-Y. Lei, Q.-Y. Leib, D.A. Leiro, J. Lemasters, J.J. Lemoine, A. Lesniak, M.S. Lev, D. Levenson, V.V. Levine, B. Levy, E. Li, F. Li, J.-L. Li, L. Li, S. Li, W. Li, X.-J. Li, Y.-B. Li, Y.-P. Liang, C. Liang, Q. Liao, Y.-F. Liberski, P.P. Lieberman, A. Lim, H.J. Lim, K.-L. Lim, K. Lin, C.-F. Lin, F.-C. Lin, J. Lin, J.D. Lin, K. Lin, W.-W. Lin, W.-C. Lin, Y.-L. Linden, R. Lingor, P. Lippincott-Schwartz, J. Lisanti, M.P. Liton, P.B. Liu, B. Liu, C.-F. Liu, K. Liu, L. Liu, Q.A. Liu, W. Liu, Y.-C. Liu, Y. Lockshin, R.A. Lok, C.-N. Lonial, S. Loos, B. Lopez-Berestein, G. López-Otín, C. Lossi, L. Lotze, M.T. Lõw, P. Lu, B. Lu, B. Lu, B. Lu, Z. Luciano, F. Lukacs, N.W. Lund, A.H. Lynch-Day, M.A. Ma, Y. Macian, F. MacKeigan, J.P. Macleod, K.F. Madeo, F. Maiuri, L. Maiuri, M.C. Malagoli, D. Malicdan, M.C.V. Malorni, W. Man, N. Mandelkow, E.-M. Manon, S. Manov, I. Mao, K. Mao, X. Mao, Z. Marambaud, P. Marazziti, D. Marcel, Y.L. Marchbank, K. Marchetti, P. Marciniak, S.J. Marcondes, M. Mardi, M. Marfe, G. Mariño, G. Markaki, M. Marten, M.R. Martin, S.J. Martinand-Mari, C. Martinet, W. Martinez-Vicente, M. Masini, M. Matarrese, P. Matsuo, S. Matteoni, R. Mayer, A. Mazure, N.M. McConkey, D.J. McConnell, M.J. McDermott, C. McDonald, C. McInerney, G.M. McKenna, S.L. McLaughlin, B. McLean, P.J. McMaster, C.R. McQuibban, G.A. Meijer, A.J. Meisler, M.H. Meléndez, A. Melia, T.J. Melino, G. Mena, M.A. Menendez, J.A. Menna-Barreto, R.F.S. Menon, M.B. Menzies, F.M. Mercer, C.A. Merighi, A. Merry, D.E. Meschini, S. Meyer, C.G. Meyer, T.F. Miao, C.-Y. Miao, J.-Y. Michels, P.A.M. Michiels, C. Mijaljica, D. Milojkovic, A. Minucci, S. Miracco, C. Miranti, C.K. Mitroulis, I. Miyazawa, K. Mizushima, N. Mograbi, B. Mohseni, S. Molero, X. Mollereau, B. Mollinedo, F. Momoi, T. Monastyrska, I. Monick, M.M. Monteiro, M.J. Moore, M.N. Mora, R. Moreau, K. Moreira, P.I. Moriyasu, Y. Moscat, J. Mostowy, S. Mottram, J.C. Motyl, T. Moussa, C.E.-H. Müller, S. Muller, S. Münger, K. Münz, C. Murphy, L.O. Murphy, M.E. Musarò, A. Mysorekar, I. Nagata, E. Nagata, K. Nahimana, A. Nair, U. Nakagawa, T. Nakahira, K. Nakano, H. Nakatogawa, H. Nanjundan, M. Naqvi, N.I. Narendra, D.P. Narita, M. Navarro, M. Nawrocki, S.T. Nazarko, T.Y. Nemchenko, A. Netea, M.G. Neufeld, T.P. Ney, P.A. Nezis, I.P. Nguyen, H.P. Nie, D. Nishino, I. Nislow, C. Nixon, R.A. Noda, T. Noegel, A.A. Nogalska, A. Noguchi, S. Notterpek, L. Novak, I. Nozaki, T. Nukina, N. Nürnberger, T. Nyfeler, B. Obara, K. Oberley, T.D. Oddo, S. Ogawa, M. Ohashi, T. Okamoto, K. Oleinick, N.L. Oliver, F.J. Olsen, L.J. Olsson, S. Opota, O. Osborne, T.F. Ostrander, G.K. Otsu, K. Ou, J.-H.J. Ouimet, M. Overholtzer, M. Ozpolat, B. Paganetti, P. Pagnini, U. Pallet, N. Palmer, G.E. Palumbo, C. Pan, T. Panaretakis, T. Pandey, U.B. Papackova, Z. Papassideri, I. Paris, I. Park, J. Park, O.K. Parys, J.B. Parzych, K.R. Patschan, S. Patterson, C. Pattingre, S. Pawelek, J.M. Peng, J. Perlmutter, D.H. Perrotta, I. Perry, G. Pervaiz, S. Peter, M. Peters, G.J. Petersen, M. Petrovski, G. Phang, J.M. Piacentini, M. Pierre, P. Pierrefite-Carle, V. Pierron, G. Pinkas-Kramarski, R. Piras, A. Piri, N. Platanias, L.C. Pöggeler, S. Poirot, M. Poletti, A. Poüs, C. Pozuelo-Rubio, M. Prætorius-Ibba, M. Prasad, A. Prescott, M. Priault, M. Produit-Zengaffinen, N. Progulske-Fox, A. Proikas-Cezanne, T. Przedborski, S. Przyklenk, K. Puertollano, R. Puyal, J. Qian, S.-B. Qin, L. Qin, Z.-H. Quaggin, S.E. Raben, N. Rabinowich, H. Rabkin, S.W. Rahman, I. Rami, A. Ramm, G. Randall, G. Randow, F. Rao, V.A. Rathmell, J.C. Ravikumar, B. Ray, S.K. Reed, B.H. Reed, J.C. Reggiori, F. Régnier-Vigouroux, A. Reichert, A.S. Reiners Jr., J.J. Reiter, R.J. Ren, J. Revuelta, J.L. Rhodes, C.J. Ritis, K. Rizzo, E. Robbins, J. Roberge, M. Roca, H. Roccheri, M.C. Rocchi, S. Rodemann, H.P. De Córdoba, S.R. Rohrer, B. Roninson, I.B. Rosen, K. Rost-Roszkowska, M.M. Rouis, M. Rouschop, K.M.A. Rovetta, F. Rubin, B.P. Rubinsztein, D.C. Ruckdeschel, K. Rucker III, E.B. Rudich, A. Rudolf, E. Ruiz-Opazo, N. Russo, R. Rusten, T.E. Ryan, K.M. Ryter, S.W. Sabatini, D.M. Sadoshima, J. Saha, T. Saitoh, T. Sakagami, H. Sakai, Y. Salekdeh, G.H. Salomoni, P. Salvaterra, P.M. Salvesen, G. Salvioli, R. Sanchez, A.M.J. Sánchez-Alcázar, J.A. Sánchez-Prieto, R. Sandri, M. Sankar, U. Sansanwal, P. Santambrogio, L. Saran, S. Sarkar, S. Sarwal, M. Sasakawa, C. Sasnauskiene, A. Sass, M. Sato, K. Sato, M. Schapira, A.H.V. Scharl, M. Schätzl, H.M. Scheper, W. Schiaffino, S. Schneider, C. Schneider, M.E. Schneider-Stock, R. Schoenlein, P.V. Schorderet, D.F. Schüller, C. Schwartz, G.K. Scorrano, L. Sealy, L. Seglen, P.O. Segura-Aguilar, J. Seiliez, I. Seleverstov, O. Sell, C. Seo, J.B. Separovic, D. Setaluri, V. Setoguchi, T. Settembre, C. Shacka, J.J. Shanmugam, M. Shapiro, I.M. Shaulian, E. Shaw, R.J. Shelhamer, J.H. Shen, H.-M. Shen, W.-C. Sheng, Z.-H. Shi, Y. Shibuya, K. Shidoji, Y. Shieh, J.-J. Shih, C.-M. Shimada, Y. Shimizu, S. Shintani, T. Shirihai, O.S. Shore, G.C. Sibirny, A.A. Sidhu, S.B. Sikorska, B. Silva-Zacarin, E.C.M. Simmons, A. Simon, A.K. Simon, H.-U. Simone, C. Simonsen, A. Sinclair, D.A. Singh, R. Sinha, D. Sinicrope, F.A. Sirko, A. Siu, P.M. Sivridis, E. Skop, V. Skulachev, V.P. Slack, R.S. Smaili, S.S. Smith, D.R. Soengas, M.S. Soldati, T. Song, X. Sood, A.K. Soong, T.W. Sotgia, F. Spector, S.A. Spies, C.D. Springer, W. Srinivasula, S.M. Stefanis, L. Steffan, J.S. Stendel, R. Stenmark, H. Stephanou, A. Stern, S.T. Sternberg, C. Stork, B. Strålfors, P. Subauste, C.S. Sui, X. Sulzer, D. Sun, J. Sun, S.-Y. Sun, Z.-J. Sung, J.J.Y. Suzuki, K. Suzuki, T. Swanson, M.S. Swanton, C. Sweeney, S.T. Sy, L.-K. Szabadkai, G. Tabas, I. Taegtmeyer, H. Tafani, M. Takács-Vellai, K. Takano, Y. Takegawa, K. Takemura, G. Takeshita, F. Talbot, N.J. Tan, K.S.W. Tanaka, K. Tanaka, K. Tang, D. Tang, D. Tanida, I. Tannous, B.A. Tavernarakis, N. Taylor, G.S. Taylor, G.A. Taylor, J.P. Terada, A.S. Terman, A. Tettamanti, G. Thevissen, K. Thompson, C.B. Thorburn, A. Thumm, M. Tian, F. Tian, Y. Tocchini-Valentini, G. Tolkovsky, A.M. Tomino, Y. Tönges, L. Tooze, S.A. Tournier, C. Tower, J. Towns, R. Trajkovic, V. Travassos, L.H. Tsai, T.-F. Tschan, M.P. Tsubata, T. 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Abstract

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field. © 2012 Landes Bioscience.

Published
2012

6. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.

Author

Blanchard, M.G., Willemsen, M.H., Walker, J.B., Dib-Hajj, S.D., Waxman, S.G., Jongmans, M.C.J., Kleefstra, T., Warrenburg, B.P.C. van de, Praamstra, P., Nicolai, J., Yntema, H.G., Bindels, R.J., Meisler, M.H., Kamsteeg, E.J., Blanchard, M.G., Willemsen, M.H., Walker, J.B., Dib-Hajj, S.D., Waxman, S.G., Jongmans, M.C.J., Kleefstra, T., Warrenburg, B.P.C. van de, Praamstra, P., Nicolai, J., Yntema, H.G., Bindels, R.J., Meisler, M.H., and Kamsteeg, E.J.

Abstract

1 mei 2015, Item does not contain fulltext, BACKGROUND: Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. METHODS: The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses. RESULTS: The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. CONCLUSIONS: Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.

Published
2015

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