33 results on '"Maubaret C"'
Search Results
2. TELOMERES ARE SHORTER IN PATIENTS WITH POLYGENIC AND MONOGENIC FORMS OF CORONARY HEART DISEASE
- Author
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Maubaret, C, Salpea, K, Jain, A, Cooper, J, Hamsten, A, Sanders, J, Montgomery, H, Neil, A, Nair, D, Humphries, SE, Consortium, HIFMECH, and Grp, S
- Published
- 2010
3. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
- Author
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Hysi, P.G. (Pirro), Cheng, C-Y. (Ching-Yu), Springelkamp, H. (Henriët), MacGregor, S. (Stuart), Bailey, J.N.C. (Jessica N. Cooke), Wojciechowski, R. (Robert), Vitart, V. (Veronique), Nag, A. (Abhishek), Hewit, A.W. (Alex), Höhn, R. (René), Venturini, C. (Cristina), Mirshahi, A. (Alireza), Ramdas, W.D. (Wishal), Thorleifsson, G. (Gudmar), Vithana, E.N. (Eranga), Khor, C.C., Stefansson, A.B. (Arni B.), Liao, J. (Jie), Haines, J.L. (Jonathan), Amin, N. (Najaf), Wang, Y. (Ying), Wild, P.S. (Philipp S.), Ozel, A.B. (Ayse), Li, J., Fleck, B.W. (Brian W.), Zeller, T. (Tanja), Staffieri, S.E. (Sandra E.), Teo, Y.Y. (Yik Ying), Cuellar-Partida, G. (Gabriel), Luo, X. (Xiaoyan), Allingham, R.R. (R Rand), Richards, J.E. (Julia), Senft, A. (Andrea), Karssen, L.C. (Lennart), Zheng, Y. (Yingfeng), Bellenguez, C. (Céline), Xu, L. (Liang), Iglesias González, A.I. (Adriana), Wilson, J.F. (James F), Kang, J.H. (Jae), Leeuwen, E.M. (Elisa) van, Jonsson, V. (Vesteinn), Thorsteinsdottir, U. (Unnur), Despriet, D.D.G. (Dominique), Ennis, S. (Sarah), Moroi, S.E. (Sayoko), Martin, N.G. (Nicholas), Jansonius, N.M. (Nomdo), Yazar, S. (Seyhan), Tai, E.S. (Shyong), Amouyel, P. (Philippe), Kirwan, J. (James), Koolwijk, L.M.E. (Leonieke) van, Hauser, M.A. (Michael), Jonasson, F. (Fridbert), Leo, P.J. (Paul), Loomis, S.J. (Stephanie J.), Fogarty, R. (Rhys), Rivadeneira Ramirez, F. (Fernando), Kearns, L.S. (Lisa S.), Lackner, K.J. (Karl), Jong, P.T.V.M. (Paulus) de, Simpson, C.L. (Claire), Pennell, C.E. (Craig), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Saw, S-M. (Seang-Mei), Lotery, A.J. (Andrew), Bailey-Wilson, J.E. (Joan E.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Maubaret, C. (Cécilia), Pfeiffer, A.F.H. (Andreas), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Young, T.L. (Terri), Pasquale, L.R. (Louis), Delcourt, C. (Cécile), Spector, T.D. (Timothy), Klaver, C.C.W. (Caroline), Small, K.S. (Kerrin), Burdon, K.P. (Kathryn), Zwart, J-A. (John-Anker), Wong, T.Y. (Tien Yin), Viswanathan, A.C. (Ananth), Mackey, D.A. (David), Craig, J.E. (Jamie), Wiggs, J.L. (Janey), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Aung, T. (Tin), Hysi, P.G. (Pirro), Cheng, C-Y. (Ching-Yu), Springelkamp, H. (Henriët), MacGregor, S. (Stuart), Bailey, J.N.C. (Jessica N. Cooke), Wojciechowski, R. (Robert), Vitart, V. (Veronique), Nag, A. (Abhishek), Hewit, A.W. (Alex), Höhn, R. (René), Venturini, C. (Cristina), Mirshahi, A. (Alireza), Ramdas, W.D. (Wishal), Thorleifsson, G. (Gudmar), Vithana, E.N. (Eranga), Khor, C.C., Stefansson, A.B. (Arni B.), Liao, J. (Jie), Haines, J.L. (Jonathan), Amin, N. (Najaf), Wang, Y. (Ying), Wild, P.S. (Philipp S.), Ozel, A.B. (Ayse), Li, J., Fleck, B.W. (Brian W.), Zeller, T. (Tanja), Staffieri, S.E. (Sandra E.), Teo, Y.Y. (Yik Ying), Cuellar-Partida, G. (Gabriel), Luo, X. (Xiaoyan), Allingham, R.R. (R Rand), Richards, J.E. (Julia), Senft, A. (Andrea), Karssen, L.C. (Lennart), Zheng, Y. (Yingfeng), Bellenguez, C. (Céline), Xu, L. (Liang), Iglesias González, A.I. (Adriana), Wilson, J.F. (James F), Kang, J.H. (Jae), Leeuwen, E.M. (Elisa) van, Jonsson, V. (Vesteinn), Thorsteinsdottir, U. (Unnur), Despriet, D.D.G. (Dominique), Ennis, S. (Sarah), Moroi, S.E. (Sayoko), Martin, N.G. (Nicholas), Jansonius, N.M. (Nomdo), Yazar, S. (Seyhan), Tai, E.S. (Shyong), Amouyel, P. (Philippe), Kirwan, J. (James), Koolwijk, L.M.E. (Leonieke) van, Hauser, M.A. (Michael), Jonasson, F. (Fridbert), Leo, P.J. (Paul), Loomis, S.J. (Stephanie J.), Fogarty, R. (Rhys), Rivadeneira Ramirez, F. (Fernando), Kearns, L.S. (Lisa S.), Lackner, K.J. (Karl), Jong, P.T.V.M. (Paulus) de, Simpson, C.L. (Claire), Pennell, C.E. (Craig), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Saw, S-M. (Seang-Mei), Lotery, A.J. (Andrew), Bailey-Wilson, J.E. (Joan E.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Maubaret, C. (Cécilia), Pfeiffer, A.F.H. (Andreas), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Young, T.L. (Terri), Pasquale, L.R. (Louis), Delcourt, C. (Cécile), Spector, T.D. (Timothy), Klaver, C.C.W. (Caroline), Small, K.S. (Kerrin), Burdon, K.P. (Kathryn), Zwart, J-A. (John-Anker), Wong, T.Y. (Tien Yin), Viswanathan, A.C. (Ananth), Mackey, D.A. (David), Craig, J.E. (Jamie), Wiggs, J.L. (Janey), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), and Aung, T. (Tin)
- Abstract
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10 '8 for rs6445055), two on chromosome 9 (P = 2.80 × 10 '11 for rs2472493 near ABCA1 and P = 6.39 × 10 '11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10 '11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
- Published
- 2014
- Full Text
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4. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma
- Author
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Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, Aung, T, Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, and Aung, T
- Abstract
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
- Published
- 2014
5. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
- Author
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Klebe, S., Golmard, J.L., Nalls, M.A., Saad, M., Singleton, A.B., Bras, J.M., Hardy, J., Simon-Sanchez, J., Heutink, P., Kuhlenbaumer, G., Charfi, R., Klein, C., Hagenah, J., Gasser, T., Wurster, I., Lesage, S., Lorenz, D., Deuschl, G., Durif, F., Pollak, P., Damier, P., Tison, F., Durr, A., Amouyel, P., Lambert, J.C., Tzourio, C., Maubaret, C., Charbonnier-Beaupel, F., Tahiri, K., Vidailhet, M., Martinez, M., Brice, A., Corvol, J.C., Bloem, B.R., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, et al., Klebe, S., Golmard, J.L., Nalls, M.A., Saad, M., Singleton, A.B., Bras, J.M., Hardy, J., Simon-Sanchez, J., Heutink, P., Kuhlenbaumer, G., Charfi, R., Klein, C., Hagenah, J., Gasser, T., Wurster, I., Lesage, S., Lorenz, D., Deuschl, G., Durif, F., Pollak, P., Damier, P., Tison, F., Durr, A., Amouyel, P., Lambert, J.C., Tzourio, C., Maubaret, C., Charbonnier-Beaupel, F., Tahiri, K., Vidailhet, M., Martinez, M., Brice, A., Corvol, J.C., Bloem, B.R., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, and et al.
- Abstract
Item does not contain fulltext, The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1+/-13.9, p=0.03) than the Val/Met (57.4+/-13.9) and the Met/Met genotypes (58.3+/-13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
- Published
- 2013
6. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
- Author
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Klebe, S. (Stephan), Golmard, L. (Lisa), Nalls, M.A. (Michael), Saad, F. (Fred), Singleton, A. (Andrew), Bras, J. (Jose), Hardy, J. (John), Simón-Sánchez, J. (Javier), Heutink, P. (Peter), Kuhlenbäumer, G. (Gregor), Charfi, R. (Rim), Klein, C. (Christoph), Hagenah, J., Gasser, T. (Thomas), Wurster, K.D. (Kathrin), Lesage, S. (Suzanne), Lorenz, D. (Delia), Deuschl, G. (Günther), Durif, F. (Franck), Pollak, M.N. (Michael), Damier, P. (Philippe), Tison, F. (François), Durr, A., Amouyel, P. (Philippe), Lambert, J.C. (Jean Charles), Tzourio, C. (Christophe), Maubaret, C. (Cécilia), Charbonnier-Beaupel, F. (Fanny), Tahiri, K. (Khadija), Vidailhet, M. (M.), Martinez, M. (Maria), Brice, A., Corvol, J.C. (Jean-Christophe), Agid, Y. (Yves), Anheim, M. (M.), Bonnet, A.-M. (A.), Borg, M. (Michael), Broussolle, E. (E.), Corvol, J.C. (Jean Christophe), Damier, Ph. (Ph), Destée, A. (A.), Durif, F. (F.), Klebe, S. (S.), Lohmann, E. (E.), Penet, C. (C.), Krack, P. (P.), Rascol, O. (O.), Tison, F. (F.), Tranchant, C. (C.), Vérin, M. (M.), Viallet, F. (F.), Vidailhet, M. (Marie), Plagnol, V. (Vincent), Bras, J.M. (Jose), Hernandez, D.G. (Dena), Sharma, M., Sheerin, U.-M. (Una-Marie), Schulte, C. (Claudia), Sveinbjörnsdóttir, S. (Sigurlaug), Arepalli, S. (Sampath), Band, G. (Gavin), Vukcevic, D. (Damjan), Barker, R.A. (Roger), Bellinguez, C. (Céline), Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Berg, D. (Daniela), Bhatia, K.P. (Kailash), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Bloem, B. (Bas), Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Brockmann, K., Brooks, J. (Janet), Burn, D.J. (David), Charlesworth, K. (Kate), Chen, H. (Honglei), Chinnery, P.F. (Patrick), Chong, S. (Sean), Clarke, C.E. (Carl), Cookson, M.R. (Mark), Cooper, J.M. (J. Mark), Counsell, C. (Carl), Dartigues, J.-F., Deloukas, P. (Panagiotis), Dexter, D.T. (David), Dijk, K.D. (Karin) van, Dillman, A. (Allissa), Durif, F. (Frank), Edkins, T. (Ted), Evans, J. (Jonathan Mark), Foltynie, T. (Thomas), Freeman, C. (Colin), Gao, J. (Jianjun), Gardner, M. (Mac), Gibbs, J. (Raphael), Goate, A.M. (Alison), Gray, E. (Emma), Guerreiro, R. (Rita), Gustafsson, O. (Omar), Harris, C. (Clare), Hellenthal, F.A., Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Huber, H. (Heiko), Hudson, G. (Gavin), Hunt, S.E. (Sarah), Huttenlocher, J. (Johanna), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Langford, C. (Cordelia), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., McNeill, N.H. (Nathan), Moorby, C. (Catriona), Moore, M. (Matt), Morris, H. (Huw), Morrison, K.E. (Karen), Mudanohwo, E. (Ese), O'Sullivan, S.S. (Sean), Pearson, J. (Justin), Pearson, R. (Ruth), Perlmutter, J.S. (Joel), Pétursson, H. (Hjörvar), Pirinen, M. (Matti), Post, B. (Bart), Ravina, B. (Bernard), Revesz, T. (Tamas), Riess, O. (Olaf), Rivadeneira Ramirez, F. (Fernando), Rizzu, P. (Patrizia), Ryten, M. (Mina), Sawcer, S.J. (Stephen), Schapira, A.H.V. (Anthony), Scheffer, H. (Hans), Shaw, K. (Karen), Shoulson, I. (Ira), Sidransky, E. (Ellen), Silva, R. (Rohan) de, Smith, C. (Colin), Spencer, C.C.A. (Chris C.), Stefansson, H. (Hreinn), Wolf, C. (Christiane), Stockton, J.D. (Joanna), Strange, A. (Amy), Su, Z. (Zhan), Talbot, D., Tanner, C.M. (Carlie), Tashakkori-Ghanbaria, A. (Avazeh), Trabzuni, D. (Danyah), Traynor, B.J. (Bryan), Uitterlinden, A.G. (André), Vandrovcova, J. (Jana), Velseboer, D. (Daan), Walker, R. (Robert), Warrenburg, B. (Bart) van de, Weale, M.E. (Michael), Wickremaratchi, M. (Mirdhu), Williams, N. (Nigel), Williams-Gray, C.H. (Caroline), Winder-Rhodes, S. (Sophie), Zwart, J-A. (John-Anker), Wood, N.W. (Nicholas), Klebe, S. (Stephan), Golmard, L. (Lisa), Nalls, M.A. (Michael), Saad, F. (Fred), Singleton, A. (Andrew), Bras, J. (Jose), Hardy, J. (John), Simón-Sánchez, J. (Javier), Heutink, P. (Peter), Kuhlenbäumer, G. (Gregor), Charfi, R. (Rim), Klein, C. (Christoph), Hagenah, J., Gasser, T. (Thomas), Wurster, K.D. (Kathrin), Lesage, S. (Suzanne), Lorenz, D. (Delia), Deuschl, G. (Günther), Durif, F. (Franck), Pollak, M.N. (Michael), Damier, P. (Philippe), Tison, F. (François), Durr, A., Amouyel, P. (Philippe), Lambert, J.C. (Jean Charles), Tzourio, C. (Christophe), Maubaret, C. (Cécilia), Charbonnier-Beaupel, F. (Fanny), Tahiri, K. (Khadija), Vidailhet, M. (M.), Martinez, M. (Maria), Brice, A., Corvol, J.C. (Jean-Christophe), Agid, Y. (Yves), Anheim, M. (M.), Bonnet, A.-M. (A.), Borg, M. (Michael), Broussolle, E. (E.), Corvol, J.C. (Jean Christophe), Damier, Ph. (Ph), Destée, A. (A.), Durif, F. (F.), Klebe, S. (S.), Lohmann, E. (E.), Penet, C. (C.), Krack, P. (P.), Rascol, O. (O.), Tison, F. (F.), Tranchant, C. (C.), Vérin, M. (M.), Viallet, F. (F.), Vidailhet, M. (Marie), Plagnol, V. (Vincent), Bras, J.M. (Jose), Hernandez, D.G. (Dena), Sharma, M., Sheerin, U.-M. (Una-Marie), Schulte, C. (Claudia), Sveinbjörnsdóttir, S. (Sigurlaug), Arepalli, S. (Sampath), Band, G. (Gavin), Vukcevic, D. (Damjan), Barker, R.A. (Roger), Bellinguez, C. (Céline), Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Berg, D. (Daniela), Bhatia, K.P. (Kailash), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Bloem, B. (Bas), Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Brockmann, K., Brooks, J. (Janet), Burn, D.J. (David), Charlesworth, K. (Kate), Chen, H. (Honglei), Chinnery, P.F. (Patrick), Chong, S. (Sean), Clarke, C.E. (Carl), Cookson, M.R. (Mark), Cooper, J.M. (J. Mark), Counsell, C. (Carl), Dartigues, J.-F., Deloukas, P. (Panagiotis), Dexter, D.T. (David), Dijk, K.D. (Karin) van, Dillman, A. (Allissa), Durif, F. (Frank), Edkins, T. (Ted), Evans, J. (Jonathan Mark), Foltynie, T. (Thomas), Freeman, C. (Colin), Gao, J. (Jianjun), Gardner, M. (Mac), Gibbs, J. (Raphael), Goate, A.M. (Alison), Gray, E. (Emma), Guerreiro, R. (Rita), Gustafsson, O. (Omar), Harris, C. (Clare), Hellenthal, F.A., Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Huber, H. (Heiko), Hudson, G. (Gavin), Hunt, S.E. (Sarah), Huttenlocher, J. (Johanna), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Langford, C. (Cordelia), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., McNeill, N.H. (Nathan), Moorby, C. (Catriona), Moore, M. (Matt), Morris, H. (Huw), Morrison, K.E. (Karen), Mudanohwo, E. (Ese), O'Sullivan, S.S. (Sean), Pearson, J. (Justin), Pearson, R. (Ruth), Perlmutter, J.S. (Joel), Pétursson, H. (Hjörvar), Pirinen, M. (Matti), Post, B. (Bart), Ravina, B. (Bernard), Revesz, T. (Tamas), Riess, O. (Olaf), Rivadeneira Ramirez, F. (Fernando), Rizzu, P. (Patrizia), Ryten, M. (Mina), Sawcer, S.J. (Stephen), Schapira, A.H.V. (Anthony), Scheffer, H. (Hans), Shaw, K. (Karen), Shoulson, I. (Ira), Sidransky, E. (Ellen), Silva, R. (Rohan) de, Smith, C. (Colin), Spencer, C.C.A. (Chris C.), Stefansson, H. (Hreinn), Wolf, C. (Christiane), Stockton, J.D. (Joanna), Strange, A. (Amy), Su, Z. (Zhan), Talbot, D., Tanner, C.M. (Carlie), Tashakkori-Ghanbaria, A. (Avazeh), Trabzuni, D. (Danyah), Traynor, B.J. (Bryan), Uitterlinden, A.G. (André), Vandrovcova, J. (Jana), Velseboer, D. (Daan), Walker, R. (Robert), Warrenburg, B. (Bart) van de, Weale, M.E. (Michael), Wickremaratchi, M. (Mirdhu), Williams, N. (Nigel), Williams-Gray, C.H. (Caroline), Winder-Rhodes, S. (Sophie), Zwart, J-A. (John-Anker), and Wood, N.W. (Nicholas)
- Abstract
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson’s disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polym
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- 2013
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7. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
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Klebe, S, Golmard, JL, Nalls, MA, Saad, M, Singleton, AB, Bras, JM, Hardy, J, Simon-Sanchez, J, Heutink, P, Kuhlenbaumer, G, Charfi, R, Klein, C, Hagenah, J, Gasser, T, Wurster, I, Lesage, S, Lorenz, D, Deuschl, G, Durif, F, Pollak, P, Damier, P, Tison, F, Durr, A, Amouyel, P, Lambert, JC, Tzourio, C, Maubaret, C, Charbonnier-Beaupel, F, Tahiri, K (Khadija), Vidailhet, M, Martinez, M, Brice, A, Corvol, JC, Klebe, S, Golmard, JL, Nalls, MA, Saad, M, Singleton, AB, Bras, JM, Hardy, J, Simon-Sanchez, J, Heutink, P, Kuhlenbaumer, G, Charfi, R, Klein, C, Hagenah, J, Gasser, T, Wurster, I, Lesage, S, Lorenz, D, Deuschl, G, Durif, F, Pollak, P, Damier, P, Tison, F, Durr, A, Amouyel, P, Lambert, JC, Tzourio, C, Maubaret, C, Charbonnier-Beaupel, F, Tahiri, K (Khadija), Vidailhet, M, Martinez, M, Brice, A, and Corvol, JC
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- 2013
8. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.
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Khanna, H., Davis, E.E., Murga-Zamalloa, C.A., Estrada-Cuzcano, A., Lopez, I., Hollander, A.I. den, Zonneveld-Vrieling, M.N., Othman, M.I., Waseem, N., Chakarova, C., Maubaret, C., Diaz-Font, A., Macdonald, I., Muzny, D.M., Wheeler, D.A., Morgan, M., Lewis, L.R., Logan, C.V., Tan, P.L., Beer, M.A., Inglehearn, C.F., Lewis, R.A., Jacobson, S.G., Bergmann, C., Beales, P.L., Attie-Bitach, T., Johnson, C.A., Otto, E.A., Bhattacharya, S.S., Hildebrandt, F., Gibbs, R.A., Koenekoop, R.K., Swaroop, A., Katsanis, N., Khanna, H., Davis, E.E., Murga-Zamalloa, C.A., Estrada-Cuzcano, A., Lopez, I., Hollander, A.I. den, Zonneveld-Vrieling, M.N., Othman, M.I., Waseem, N., Chakarova, C., Maubaret, C., Diaz-Font, A., Macdonald, I., Muzny, D.M., Wheeler, D.A., Morgan, M., Lewis, L.R., Logan, C.V., Tan, P.L., Beer, M.A., Inglehearn, C.F., Lewis, R.A., Jacobson, S.G., Bergmann, C., Beales, P.L., Attie-Bitach, T., Johnson, C.A., Otto, E.A., Bhattacharya, S.S., Hildebrandt, F., Gibbs, R.A., Koenekoop, R.K., Swaroop, A., and Katsanis, N.
- Abstract
Contains fulltext : 81600.pdf (publisher's version ) (Closed access), Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.
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- 2009
9. Devenir nonagénaire : facteurs associés à la survie jusqu’à l’âge de 90ans chez des septuagénaires de la cohorte prospective PAQUID
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Edjolo, A., primary, Helmer, C., additional, Barberger-Gateau, P., additional, Dartigues, J.-F., additional, Maubaret, C., additional, and Peres, K., additional
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- 2013
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10. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.
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Chakarova, CF, Papaioannou, MG, Khanna, H, Lopez, I, Waseem, N, Shah, A, Theis, T, Friedman, J, Maubaret, C, Bujakowska, K, Veraitch, B, Abd El-Aziz, MM, Prescott, DQ, Parapuram, SK, Bickmore, WA, Munro, PMG, Gal, A, Hamel, CP, Marigo, V, Ponting, CP, Wissinger, B, Zrenner, E, Matter, K, Swaroop, A, Koenekoop, RK, Bhattacharya, SS, Chakarova, CF, Papaioannou, MG, Khanna, H, Lopez, I, Waseem, N, Shah, A, Theis, T, Friedman, J, Maubaret, C, Bujakowska, K, Veraitch, B, Abd El-Aziz, MM, Prescott, DQ, Parapuram, SK, Bickmore, WA, Munro, PMG, Gal, A, Hamel, CP, Marigo, V, Ponting, CP, Wissinger, B, Zrenner, E, Matter, K, Swaroop, A, Koenekoop, RK, and Bhattacharya, SS
- Abstract
We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families--one French Canadian and one German family, respectively. Interestingly, a distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, which was found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase and localizes in the nucleus in speckled loci that are associated with promyelocytic leukemia bodies. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect, as the molecular mechanism of the disease and make rescue of the clinical phenotype amenable to somatic gene therapy.
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- 2007
11. MS443 THE ARG399GLN VARIANT IN THE DNA REPAIR ENZYME XRCC1 IS ASSOCIATED WITH INCREASED GENETIC INSTABILITY IN PATIENTS WITH ATHEROSCLEROSIS
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Federici, C., primary, Li, K., additional, Salpea, K., additional, Maubaret, C., additional, Humphries, S.E., additional, and Andreassi, M.G., additional
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- 2010
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12. THE COMMON FUNCTIONAL ARG399GLN VARIANT IN THE DNA REPAIR ENZYME XRCC1 IS ASSOCIATED WITH ELEVATED LEVELS OF MICRONUCLEUS CHROMOSOMAL DNA DAMAGE AND SHORTER TELOMERE LENGTH IN PATIENT WITH ATHEROSCLEROSIS
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Federici, C., primary, Manfredi, S., additional, Del Fiandra, M., additional, Salpea, K., additional, Maubaret, C., additional, Humphries, S.E., additional, and Andreassi, M.G., additional
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- 2009
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13. Abstract: P794 TELOMERES ARE SHORTER IN MI AND CABG PATIENTS COMPARED TO HEALTHY SUBJECTS; CORRELATION WITH ENVIRONMENTAL AND GENETIC RISK FACTORS
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Maubaret, C, primary, Salpea, K, additional, Cooper, J, additional, Consortium, HIFMECH, additional, Sanders, J, additional, Montgomery, H, additional, and Humphries, S, additional
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- 2009
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14. Génétique des rétinites pigmentaires : classification métabolique et corrélations phénotype/génotype
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Maubaret, C., primary and Hamel, C., additional
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- 2005
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15. Devenir nonagénaire : facteurs associés à la survie jusqu’à l’âge de 90 ans chez des septuagénaires de la cohorte prospective PAQUID
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Edjolo, A., Helmer, C., Barberger-Gateau, P., Dartigues, J.-F., Maubaret, C., and Peres, K.
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- 2013
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16. Functional characterization of a novel c.614-622del rhodopsin mutation in a French pedigree with retinitis pigmentosa
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Maubaret, C., Kosmaoglou, M., Low, S., Chakarova, C. F., Bidot, S., Thauvin-Robinet, C., Robson, A. G., Waseem, N., Michael Cheetham, and Bhattacharya, S. S.
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Rhodopsin ,Adolescent ,Base Sequence ,Genetic Linkage ,Molecular Sequence Data ,Exons ,Sequence Analysis, DNA ,Middle Aged ,White People ,Cell Line ,Pedigree ,Transformation, Genetic ,Case-Control Studies ,Humans ,Female ,France ,Proteostasis Deficiencies ,Retinitis Pigmentosa ,Research Article ,Genes, Dominant ,Microsatellite Repeats ,Plasmids ,Sequence Deletion - Abstract
Purpose To identify and functionally characterize the mutation responsible for autosomal dominant retinitis pigmentosa (adRP) in a large, six-generation French family. Methods Twenty individuals from this family participated in the genetic investigation. Six affected and 14 unaffected individuals from three-generations were available for linkage analysis using microsatellite markers flanking the rhodopsin (RHO) gene. A two-point logarithm of odds (LOD) score calculation was undertaken using GENEMARKER and MLINK software. Sanger sequencing of RHO was performed. Cellular localization of the mutant protein was performed by transforming SK-N-SH cells with pEGFP-N1-Rho, pEGFP-N1-Rho(P23H), and pEGFP-N1-Rho(c.614–622del). Results The proband had nyctalopia, visual field constriction, peripheral bone spicule pigmentation of the fundus, central acuity (6/24 RE; 6/12 LE) at 55 years of age. Linkage analysis of this family suggested RHO as a possible candidate since the flanking marker D3S1292 yielded a LOD score of 2.43 at θ=0. Cloning of an exon 3 PCR product and direct sequencing of single clones identified a novel deletion in the third exon of RHO, c.614–622del (p.Y206-F208del). The deleted mutant protein localized to the endoplasmic reticulum and formed inclusion bodies. Conclusions This novel deletion in exon 3 of the RHO gene, c.614–622del results in a classical form of adRP in a multi-generation French family. Protein expression analyses confirmed that the deletion led to protein misfolding and suggest this is a class II mutation, similar to P23H, the most common class II mutation seen in North America.
17. Health and aging in elderly farmers: the AMI cohort
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Pérès Karine, Matharan Fanny, Allard Michèle, Amieva Hélène, Baldi Isabelle, Barberger-Gateau Pascale, Bergua Valérie, Bourdel-Marchasson Isabelle, Delcourt Cécile, Foubert-Samier Alexandra, Fourrier-Réglat Annie, Gaimard Maryse, Laberon Sonia, Maubaret Cécilia, Postal Virginie, Chantal Chantal, Rainfray Muriel, Rascle Nicole, and Dartigues Jean-François
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Aging ,Rural health ,Agriculture ,Cohort studies ,Interdisciplinary studies ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. Methods/design The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South-Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson’s disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry…). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). Discussion AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach.
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- 2012
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18. Detection of CTX-M-15 ESBL in XDR Haemophilus parainfluenzae from a urethral swab.
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Caméléna F, Merimèche M, Liberge M, Maubaret C, Donay JL, Taha MK, Fouéré S, and Berçot B
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- Phylogeny, Amino Acid Substitution, beta-Lactamases genetics, Haemophilus parainfluenzae genetics, Anti-Bacterial Agents pharmacology
- Abstract
Objectives: Haemophilus parainfluenzae is an opportunistic pathogen causing respiratory tract infection and sexually transmitted diseases. The emergence of multidrug resistance in this species is particularly worrisome, especially since the recent description of CTX-M-15 ESBL-producing isolates in Spain. The aim of this study was to characterize a CTX-M-15-producing H. parainfluenzae clinical isolate, HP01, obtained from a urethral swab., Methods: MICs were determined with gradient strips for this isolate. Hydrolysis assays were performed with the β LACTA test. Genomic DNA from HP01 was subjected to Illumina and Oxford Nanopore sequencing to investigate the genetic environment of blaCTX-M-15. Phylogenetic analysis was performed with available H. parainfluenzae genomes from the NCBI database, including CTX-M-15 producers., Results: HP01, an XDR isolate, was resistant to penicillin, third-generation cephalosporins, fluoroquinolones, macrolides, cyclines and co-trimoxazole and susceptible only to carbapenems and rifampicin. HP01 carried blaTEM-1, blaCTX-M-15, tet(M), catS and mef(E)/mel and harboured amino acid substitutions in PBP3, PBP5, GyrA, ParC and FolA implicated in resistance. Genomic analysis revealed that blaCTX-M-15 was carried by a Tn3-like transposon inserted into a novel integrative and conjugative element (ICE), ICEHpaSLS, present on the chromosome and belonging to the ICEHin1056 family described in Haemophilus influenzae. The tet(M)-MEGA element was also detected on the chromosome. No plasmid was found. The phylogenetic analysis showed that four H. parainfluenzae producing CTX-M-15 clustered in the same clade., Conclusions: Here we report the description of an XDR H. parainfluenzae producing blaCTX-M-15 isolated from a urethral swab. The blaCTX-M-15 gene was inserted into an ICE structure similar to those recently described in CTX-M-15 producers in Spain. The emergence of XDR H. parainfluenzae producing blaCTX-M-15 is a matter of great concern. Careful surveillance is required to prevent its spread., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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19. Two cases of extensively drug-resistant (XDR) Neisseria gonorrhoeae infection combining ceftriaxone-resistance and high-level azithromycin resistance, France, November 2022 and May 2023.
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Maubaret C, Caméléna F, Mrimèche M, Braille A, Liberge M, Mainardis M, Guillaume C, Noel F, Bébéar C, Molina JM, Lot F, Chazelle E, and Berçot B
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- Humans, Azithromycin pharmacology, France, Multilocus Sequence Typing, Neisseria gonorrhoeae genetics, Ceftriaxone pharmacology, Gonorrhea diagnosis, Gonorrhea drug therapy
- Abstract
We report two extensively drug-resistant (XDR) Neisseria gonorrhoeae (NG) isolates combining high-level resistance to azithromycin and resistance to ceftriaxone, obtained in France from two heterosexual patients, one of whom returned from Cambodia. Whole genome sequencing identified MLST ST16406, the mosaic penA -60.001 which caused ceftriaxone resistance in the internationally spreading FC428 clone, and the A2059G mutation in the 23S rRNA gene. The NG isolates F93 and F94 were related to XDR isolates detected in Austria and the United Kingdom in 2022.
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- 2023
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20. Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.
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Dhamrait SS, Maubaret C, Pedersen-Bjergaard U, Brull DJ, Gohlke P, Payne JR, World M, Thorsteinsson B, Humphries SE, and Montgomery HE
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- Adolescent, Adult, Alleles, Diabetes Mellitus, Type 1 genetics, Humans, Male, Middle Aged, Young Adult, Diabetes Mellitus, Type 1 metabolism, Gene Expression Regulation, Genetic Variation, Mitochondrial Uncoupling Proteins genetics, Peptidyl-Dipeptidase A genetics, Signal Transduction
- Abstract
Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role., (© 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.)
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- 2016
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21. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.
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Hysi PG, Cheng CY, Springelkamp H, Macgregor S, Bailey JNC, Wojciechowski R, Vitart V, Nag A, Hewitt AW, Höhn R, Venturini C, Mirshahi A, Ramdas WD, Thorleifsson G, Vithana E, Khor CC, Stefansson AB, Liao J, Haines JL, Amin N, Wang YX, Wild PS, Ozel AB, Li JZ, Fleck BW, Zeller T, Staffieri SE, Teo YY, Cuellar-Partida G, Luo X, Allingham RR, Richards JE, Senft A, Karssen LC, Zheng Y, Bellenguez C, Xu L, Iglesias AI, Wilson JF, Kang JH, van Leeuwen EM, Jonsson V, Thorsteinsdottir U, Despriet DDG, Ennis S, Moroi SE, Martin NG, Jansonius NM, Yazar S, Tai ES, Amouyel P, Kirwan J, van Koolwijk LME, Hauser MA, Jonasson F, Leo P, Loomis SJ, Fogarty R, Rivadeneira F, Kearns L, Lackner KJ, de Jong PTVM, Simpson CL, Pennell CE, Oostra BA, Uitterlinden AG, Saw SM, Lotery AJ, Bailey-Wilson JE, Hofman A, Vingerling JR, Maubaret C, Pfeiffer N, Wolfs RCW, Lemij HG, Young TL, Pasquale LR, Delcourt C, Spector TD, Klaver CCW, Small KS, Burdon KP, Stefansson K, Wong TY, Viswanathan A, Mackey DA, Craig JE, Wiggs JL, van Duijn CM, Hammond CJ, and Aung T
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- ABO Blood-Group System genetics, ATP Binding Cassette Transporter 1 genetics, Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 9 genetics, Cohort Studies, Female, Fibronectins genetics, Genotype, Glaucoma, Open-Angle genetics, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Glaucoma genetics, Intraocular Pressure genetics
- Abstract
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
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- 2014
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22. Plasma estrogen levels, estrogen receptor gene variation, and ischemic arterial disease in postmenopausal women: the three-city prospective cohort study.
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Scarabin-Carré V, Brailly-Tabard S, Ancelin ML, Maubaret C, Guiochon-Mantel A, Canonico M, and Scarabin PY
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- Aged, Aged, 80 and over, Case-Control Studies, Cities epidemiology, Female, France epidemiology, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Postmenopause genetics, Coronary Artery Disease blood, Coronary Artery Disease genetics, Estradiol blood, Estrogen Receptor alpha genetics, Estrogen Receptor beta genetics, Postmenopause blood
- Abstract
Background: In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor-α (ESR1) and -β (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated., Methods: In the Three-City prospective cohort study among subjects older than 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17β-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4 years of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for a 1-SD increase in hormones levels by the genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and a correction for multiple testing. We also investigated the role of hemostasis and inflammation as potential mediators., Results: Neither estrogens nor IAD risk was significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol [HR1.40, 95% confidence interval (CI) 1.11-1.77]. Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with the AG/GG genotype (HR 1.62, 95% CI 1.22-2.17 and HR 1.03, 95% CI 0.81-1.30, respectively; P for interaction <.05). An additional adjustment for hemostatic variables reduced the HR by about one third in women carrying the rs9340799-AA genotype (HR 1.41, 95% CI 1.06-1.90)., Conclusion: The ESR1 rs9340799 genotype may modify the IAD risk related to high endogenous estrogens levels in older postmenopausal women. Hypercoagulability may act as a mediator.
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- 2014
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23. Association of HDL-related loci with age-related macular degeneration and plasma lutein and zeaxanthin: the Alienor study.
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Merle BM, Maubaret C, Korobelnik JF, Delyfer MN, Rougier MB, Lambert JC, Amouyel P, Malet F, Le Goff M, Dartigues JF, Barberger-Gateau P, and Delcourt C
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- Age Factors, Aged, Aged, 80 and over, Female, Genotype, Humans, Lipase genetics, Lipoprotein Lipase genetics, Male, Polymorphism, Single Nucleotide genetics, Prospective Studies, Zeaxanthins, Lipoproteins, HDL genetics, Lutein blood, Macular Degeneration blood, Macular Degeneration genetics, Xanthophylls blood
- Abstract
Background: Several genes implicated in high-density lipoprotein (HDL) metabolism have been reported to be associated with age-related macular degeneration (AMD). Furthermore, HDL transport the two carotenoids, lutein and zeaxanthin, which are highly suspected to play a key-role in the protection against AMD. The objective is to confirm the associations of HDL-related loci with AMD and to assess their associations with plasma lutein and zeaxanthin concentrations., Methods: Alienor study is a prospective population-based study on nutrition and age-related eye diseases performed in 963 elderly residents of Bordeaux, France. AMD was graded according to the international classification, from non-mydriatic colour retinal photographs. Plasma lutein and zeaxanthin were determined by normal-phase high-performance liquid chromatography. The following polymorphisms were studied: rs493258 and rs10468017 (LIPC), rs3764261 (CETP), rs12678919 (LPL) and rs1883025 (ABCA1)., Results: After multivariate adjustment, the TT genotype of the LIPC rs493258 variant was significantly associated with a reduced risk for early and late AMD (OR=0.64, 95%CI: 0.41-0.99; p=0.049 and OR=0.26, 95%CI: 0.08-0.85; p=0.03, respectively), and with higher plasma zeaxanthin concentrations (p=0.03), while plasma lipids were not significantly different according to this SNP. Besides, the LPL variant was associated with early AMD (OR=0.67, 95%CI: 0.45-1.00; p=0.05) and both with plasma lipids and plasma lutein (p=0.047). Associations of LIPC rs10468017, CETP and ABCA1 polymorphisms with AMD did not reach statistical significance., Conclusion: These findings suggest that LIPC and LPL genes could both modify the risk for AMD and the metabolism of lutein and zeaxanthin.
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- 2013
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24. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism.
- Author
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Klebe S, Golmard JL, Nalls MA, Saad M, Singleton AB, Bras JM, Hardy J, Simon-Sanchez J, Heutink P, Kuhlenbäumer G, Charfi R, Klein C, Hagenah J, Gasser T, Wurster I, Lesage S, Lorenz D, Deuschl G, Durif F, Pollak P, Damier P, Tison F, Durr A, Amouyel P, Lambert JC, Tzourio C, Maubaret C, Charbonnier-Beaupel F, Tahiri K, Vidailhet M, Martinez M, Brice A, and Corvol JC
- Subjects
- Age of Onset, Aged, Genotype, Humans, Male, Middle Aged, Sex Factors, Catechol O-Methyltransferase genetics, Parkinson Disease genetics, Polymorphism, Single Nucleotide genetics
- Abstract
The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
- Published
- 2013
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25. Functional characterization of a novel c.614-622del rhodopsin mutation in a French pedigree with retinitis pigmentosa.
- Author
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Maubaret C, Kosmaoglou M, Low S, Chakarova CF, Bidot S, Thauvin-Robinet C, Robson AG, Waseem N, Cheetham ME, and Bhattacharya SS
- Subjects
- Adolescent, Case-Control Studies, Cell Line, Exons, Female, France, Genes, Dominant, Genetic Linkage, Humans, Microsatellite Repeats, Middle Aged, Molecular Sequence Data, Pedigree, Plasmids, Sequence Analysis, DNA, Transformation, Genetic, Base Sequence, Proteostasis Deficiencies genetics, Retinitis Pigmentosa genetics, Rhodopsin genetics, Sequence Deletion genetics, White People genetics
- Abstract
Purpose: To identify and functionally characterize the mutation responsible for autosomal dominant retinitis pigmentosa (adRP) in a large, six-generation French family., Methods: Twenty individuals from this family participated in the genetic investigation. Six affected and 14 unaffected individuals from three-generations were available for linkage analysis using microsatellite markers flanking the rhodopsin (RHO) gene. A two-point logarithm of odds (LOD) score calculation was undertaken using GENEMARKER and MLINK software. Sanger sequencing of RHO was performed. Cellular localization of the mutant protein was performed by transforming SK-N-SH cells with pEGFP-N1-Rho, pEGFP-N1-Rho(P23H), and pEGFP-N1-Rho(c.614-622del)., Results: The proband had nyctalopia, visual field constriction, peripheral bone spicule pigmentation of the fundus, central acuity (6/24 RE; 6/12 LE) at 55 years of age. Linkage analysis of this family suggested RHO as a possible candidate since the flanking marker D3S1292 yielded a LOD score of 2.43 at θ=0. Cloning of an exon 3 PCR product and direct sequencing of single clones identified a novel deletion in the third exon of RHO, c.614-622del (p.Y206-F208del). The deleted mutant protein localized to the endoplasmic reticulum and formed inclusion bodies., Conclusions: This novel deletion in exon 3 of the RHO gene, c.614-622del results in a classical form of adRP in a multi-generation French family. Protein expression analyses confirmed that the deletion led to protein misfolding and suggest this is a class II mutation, similar to P23H, the most common class II mutation seen in North America.
- Published
- 2012
26. Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
- Author
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Friedman JS, Chang B, Krauth DS, Lopez I, Waseem NH, Hurd RE, Feathers KL, Branham KE, Shaw M, Thomas GE, Brooks MJ, Liu C, Bakeri HA, Campos MM, Maubaret C, Webster AR, Rodriguez IR, Thompson DA, Bhattacharya SS, Koenekoop RK, Heckenlively JR, and Swaroop A
- Subjects
- 1-Acylglycerophosphocholine O-Acyltransferase metabolism, Animals, Base Sequence, Blotting, Northern, Chromatography, High Pressure Liquid, Chromosome Mapping, DNA Mutational Analysis, Humans, Immunoblotting, Leber Congenital Amaurosis genetics, Lipids analysis, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Mice, Mutant Strains, Microscopy, Electron, Transmission, Phosphatidylcholines analysis, Photoreceptor Cells, Vertebrate chemistry, Photoreceptor Cells, Vertebrate ultrastructure, Retinal Degeneration metabolism, Retinal Degeneration pathology, Retinitis Pigmentosa genetics, Reverse Transcriptase Polymerase Chain Reaction, 1-Acylglycerophosphocholine O-Acyltransferase genetics, Photoreceptor Cells, Vertebrate metabolism, Retinal Degeneration genetics
- Abstract
Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420-421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14-20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoylphosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis.
- Published
- 2010
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- View/download PDF
27. Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes.
- Author
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Towns KV, Kipioti A, Long V, McKibbin M, Maubaret C, Vaclavik V, Ehsani P, Springell K, Kamal M, Ramesar RS, Mackey DA, Moore AT, Mukhopadhyay R, Webster AR, Black GC, O'Sullivan J, Bhattacharya SS, Pierce EA, Beggs JD, and Inglehearn CF
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Mutation, Mutation, Missense, Phenotype, Prognosis, RNA-Binding Proteins, Retinitis Pigmentosa pathology, Young Adult, Carrier Proteins genetics, Retinitis Pigmentosa genetics, Yeasts genetics
- Abstract
PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
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- View/download PDF
28. Study of gene-targeted mouse models of splicing factor gene Prpf31 implicated in human autosomal dominant retinitis pigmentosa (RP).
- Author
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Bujakowska K, Maubaret C, Chakarova CF, Tanimoto N, Beck SC, Fahl E, Humphries MM, Kenna PF, Makarov E, Makarova O, Paquet-Durand F, Ekström PA, van Veen T, Leveillard T, Humphries P, Seeliger MW, and Bhattacharya SS
- Subjects
- Animals, Blotting, Western, Electrophoresis, Polyacrylamide Gel, Electroretinography, Female, Gene Knock-In Techniques, Gene Knockout Techniques, Gene Targeting, Genotype, Humans, In Situ Nick-End Labeling, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Ophthalmoscopy, Point Mutation, Retina physiopathology, Retinitis Pigmentosa physiopathology, Disease Models, Animal, Eye Proteins genetics, Genes, Dominant, Retinitis Pigmentosa genetics
- Abstract
Purpose: Pre-mRNA processing factor 31 (PRPF31) is a ubiquitous protein needed for the assembly of the pre-mRNA splicing machinery. It has been shown that mutations in this gene cause autosomal dominant retinitis pigmentosa 11 (RP11), which is characterized by rod-cell degeneration. Interestingly, mutations in this ubiquitously expressed gene do not lead to phenotypes other than retinal malfunction. Furthermore, the dominant inheritance pattern has shown incomplete penetrance, which poses interesting questions about the disease mechanism of RP11., Methods: To characterize PRPF31 function in the rod cells, two animal models have been generated. One was a heterozygous knock-in mouse (Prpf31(A216P/+)) carrying a point mutation p.A216P, which has previously been identified in RP11 patients. The second was a heterozygous knockout mouse (Prpf31(+/-)). Retinal degeneration in RP11 mouse models was monitored by electroretinography and histology., Results: Generation of the mouse models is presented, as are results of ERGs and retinal morphology. No degenerative phenotype on fundus examination was found in Prpf31(A216P/+) and Prpf31(+/-) mice. Prpf31(A216P/A216P) and Prpf31(-/-) genotypes were embryonic lethal., Conclusions: The results imply that Prpf31 is necessary for survival, and there is no compensation mechanism in mouse for the lack of this splicing factor. The authors suggest that p.A216P mutation in Prpf31 does not exert a dominant negative effect and that one Prpf31 wild-type allele is sufficient for maintenance of the healthy retina in mice.
- Published
- 2009
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- View/download PDF
29. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.
- Author
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Khanna H, Davis EE, Murga-Zamalloa CA, Estrada-Cuzcano A, Lopez I, den Hollander AI, Zonneveld MN, Othman MI, Waseem N, Chakarova CF, Maubaret C, Diaz-Font A, MacDonald I, Muzny DM, Wheeler DA, Morgan M, Lewis LR, Logan CV, Tan PL, Beer MA, Inglehearn CF, Lewis RA, Jacobson SG, Bergmann C, Beales PL, Attié-Bitach T, Johnson CA, Otto EA, Bhattacharya SS, Hildebrandt F, Gibbs RA, Koenekoop RK, Swaroop A, and Katsanis N
- Subjects
- Alleles, Animals, Bardet-Biedl Syndrome genetics, Ciliary Body physiopathology, Europe epidemiology, GTP Phosphohydrolases genetics, GTP Phosphohydrolases metabolism, Humans, Mutation, Polymorphism, Single Nucleotide, RNA, Messenger genetics, Retinal Degeneration epidemiology, Retinal Degeneration prevention & control, Retinitis Pigmentosa enzymology, Retinitis Pigmentosa genetics, Uveitis epidemiology, Uveitis genetics, Zebrafish genetics, Adaptor Proteins, Signal Transducing genetics, Genetic Variation, Retinal Degeneration genetics
- Abstract
Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.
- Published
- 2009
- Full Text
- View/download PDF
30. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.
- Author
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Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott de Q, Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP, Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, Swaroop A, Koenekoop RK, and Bhattacharya SS
- Subjects
- Adolescent, Adult, Base Sequence, Child, Chromosomes, Human, DNA Mutational Analysis, Exons genetics, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Neoplasm Proteins metabolism, Nuclear Proteins metabolism, Pedigree, Ubiquitin-Protein Ligases metabolism, Genes, Dominant, Mutation genetics, Neoplasm Proteins genetics, Nuclear Proteins genetics, Pigment Epithelium of Eye blood supply, Pigment Epithelium of Eye pathology, Retinitis Pigmentosa genetics, Ubiquitin-Protein Ligases genetics
- Abstract
We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families--one French Canadian and one German family, respectively. Interestingly, a distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, which was found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase and localizes in the nucleus in speckled loci that are associated with promyelocytic leukemia bodies. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect, as the molecular mechanism of the disease and make rescue of the clinical phenotype amenable to somatic gene therapy.
- Published
- 2007
- Full Text
- View/download PDF
31. Novel mutations in MYO7A and USH2A in Usher syndrome.
- Author
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Maubaret C, Griffoin JM, Arnaud B, and Hamel C
- Subjects
- Adolescent, Adult, Child, DNA Mutational Analysis, Dyneins, Humans, Middle Aged, Myosin VIIa, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, RNA Splice Sites genetics, Syndrome, Extracellular Matrix Proteins genetics, Hearing Loss, Sensorineural genetics, Mutation genetics, Myosins genetics, Retinitis Pigmentosa genetics
- Abstract
Purpose: Usher syndrome is an autosomal recessive disease associating retinitis pigmentosa and neurosensory deafness. Three clinical types (USH1, USH2, USH3) and 11 mutated genes or loci have been described. Mutations in MYO7A and USH2A are responsible for about 40% and 60% of Usher syndromes type 1 and 2, respectively. These genes were screened in a series of patients suffering from Usher syndrome., Methods: We performed SSCP screening of MYO7A in 12 unrelated patients suffering from Usher syndrome type 1 (USH1) and USH2A in 28 unrelated patients affected by Usher syndrome type 2 (USH2)., Results/conclusions: Six mutations in MYO7A were found in five patients, including two novel mutations c.397C > G (His133Asp) and 1244-2A > G (Glu459Stop), accounting for 42% of our USH1 patients. Twelve mutations in USH2A were found in 11 patients, including four new mutations c.850delGA, c.1841-2A > G, c.3129insT, and c.3920C > G (Ser1307Stop), accounting for 39% of our USH2 patients
- Published
- 2005
- Full Text
- View/download PDF
32. [Genetics of retinitis pigmentosa: metabolic classification and phenotype/genotype correlations].
- Author
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Maubaret C and Hamel C
- Subjects
- Genotype, Humans, Pedigree, Phenotype, Photoreceptor Cells, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa classification, Retinitis Pigmentosa genetics
- Abstract
Retinitis pigmentosa (RP, prevalence 1/4000) is a set of hereditary retinal dystrophies characterized by pigment deposits in fundus and progressive death of photoreceptors, always associated with the alteration of retinal pigment epithelium. Genetic heterogeneity of the typical nonsyndromic form (rod cone dystrophy) is extensive: 11 genes and one locus were reported for autosomal dominant RP, 17 genes and five loci for autosomal recessive RP, and two genes and two loci for X-linked RP. A survey of mutation screening reports in large series of patients indicates that the frequency of mutations for all cloned genes varies from 40% to 54% of cases in autosomal dominant RP, from 17% to 24% in autosomal recessive RP (excluding the USH2A gene for which the values remain uncertain) and from 61% to 89% in X-linked RP. Very few studies report on sporadic cases except for the two X-linked genes, RP2 and RPGR, which account for 29% of sporadic cases in males. Altogether, the two most frequently involved genes are RPGR (13% of all RP cases) and RHO (4%), an important consideration for molecular diagnosis. Finally, we roughly estimate that currently known genes do not represent more than 50% of RP cases, suggesting that many genes remain to be discovered. The known genes can be classified into metabolic groups according to the encoded protein: visual transduction, visual cycle, transcription factors, structural proteins, spliceosome complex and cellular traffic, indicating the high level of specialization of photoreceptors and of the retinal pigment epithelium. In parallel with this classification, genotype/phenotype correlations have been established that will help ophthalmologists to suspect particular genes, and thereby mechanisms. This approach will provide better informations to patients and will orient the choice of future therapies.
- Published
- 2005
- Full Text
- View/download PDF
33. Identification of preferentially expressed mRNAs in retina and cochlea.
- Author
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Maubaret C, Delettre C, Sola S, and Hamel CP
- Subjects
- Animals, Chromosome Mapping, Databases, Genetic, Expressed Sequence Tags, Gene Expression Profiling, Gene Library, Mice, Mice, Inbred C57BL, RNA, Messenger biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Cochlea metabolism, RNA, Messenger genetics, Retina metabolism
- Abstract
To search for genes that could be involved in genetic disorders primarily involving the retina and the cochlea, we tried to identify mRNAs preferentially expressed in retina and cochlea and to establish their chromosomal localization. Two approaches were employed. First, a mouse subtracted library (retina + cochlea against liver + brain) was generated. Randomly selected cDNA clones were sequenced and compared to databases. Tissue expression of some of them was analyzed by RT-PCR. Using radiation hybrid cell lines, the mouse chromosomal localization was determined for those showing the highest level in the retina and the cochlea. Second, human Expressed Sequence Tags (ESTs) with preferential expression in the retina and the cochlea were searched for in databases, and chromosomal localization was also established. From 171 sequenced clones, 73 were classified as known genes (with 17 clones coding for 6 genes), 86 were homologous to ESTs, and 12 were unidentified. Of 108 selected clones, 22 (18.5%) had the highest level of expression in the retina and/or the cochlea, while expression was higher in another tissue or ubiquitous for 60 (55.5%) and 22 (20.4%) of them, respectively. By RT-PCR, one clone similar to the mouse Asic3 cDNA (proton-gated channel) was found mainly in the retina and cochlea, but its human ortholog was widely expressed. We selected 17 ESTs from the UniGene database with restricted expression including in the retina and cochlea. We mapped 10 of these ESTs as well as four mouse clones from the subtracted library. Some of them localized to morbid intervals. The combined information from expression analysis and chromosomal localization allowed for the identification of potential candidate genes for retinal diseases (CORD8, CORD9) and syndromic blindness/deafness/renal defects.
- Published
- 2002
- Full Text
- View/download PDF
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