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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associ...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group
2016
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980482/ https://www.ncbi.nlm.nih.gov/pubmed/27503255 http://dx.doi.org/10.1038/ncomms12342 |
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| author | Rivas, Manuel A. Graham, Daniel Sulem, Patrick Stevens, Christine Desch, A. Nicole Goyette, Philippe Gudbjartsson, Daniel Jonsdottir, Ingileif Thorsteinsdottir, Unnur Degenhardt, Frauke Mucha, Sören Kurki, Mitja I. Li, Dalin D'Amato, Mauro Annese, Vito Vermeire, Severine Weersma, Rinse K. Halfvarson, Jonas Paavola-Sakki, Paulina Lappalainen, Maarit Lek, Monkol Cummings, Beryl Tukiainen, Taru Haritunians, Talin Halme, Leena Koskinen, Lotta L. E. Ananthakrishnan, Ashwin N. Luo, Yang Heap, Graham A. Visschedijk, Marijn C. MacArthur, Daniel G. Neale, Benjamin M. Ahmad, Tariq Anderson, Carl A. Brant, Steven R. Duerr, Richard H. Silverberg, Mark S. Cho, Judy H Palotie, Aarno Saavalainen, Päivi Kontula, Kimmo Färkkilä, Martti McGovern, Dermot P. B. Franke, Andre Stefansson, Kari Rioux, John D. Xavier, Ramnik J. Daly, Mark J. Barrett, J. de Lane, K. Edwards, C. Hart, A. Hawkey, C. Jostins, L. Kennedy, N. Lamb, C. Lee, J. Lees, C. Mansfield, J. Mathew, C. Mowatt, C. Newman, B. Nimmo, E. Parkes, M. Pollard, M. Prescott, N. Randall, J. Rice, D. Satsangi, J. Simmons, A. Tremelling, M. Uhlig, H. Wilson, D. Abraham, C. Achkar, J. P. Bitton, A. Boucher, G. Croitoru, K. Fleshner, P. Glas, J. Kugathasan, S. Limbergen, J. V. Milgrom, R. Proctor, D. Regueiro, M. Schumm, P. L. Sharma, Y. Stempak, J. M. Targan, S. R. Wang, M. H. |
| author_facet | Rivas, Manuel A. Graham, Daniel Sulem, Patrick Stevens, Christine Desch, A. Nicole Goyette, Philippe Gudbjartsson, Daniel Jonsdottir, Ingileif Thorsteinsdottir, Unnur Degenhardt, Frauke Mucha, Sören Kurki, Mitja I. Li, Dalin D'Amato, Mauro Annese, Vito Vermeire, Severine Weersma, Rinse K. Halfvarson, Jonas Paavola-Sakki, Paulina Lappalainen, Maarit Lek, Monkol Cummings, Beryl Tukiainen, Taru Haritunians, Talin Halme, Leena Koskinen, Lotta L. E. Ananthakrishnan, Ashwin N. Luo, Yang Heap, Graham A. Visschedijk, Marijn C. MacArthur, Daniel G. Neale, Benjamin M. Ahmad, Tariq Anderson, Carl A. Brant, Steven R. Duerr, Richard H. Silverberg, Mark S. Cho, Judy H Palotie, Aarno Saavalainen, Päivi Kontula, Kimmo Färkkilä, Martti McGovern, Dermot P. B. Franke, Andre Stefansson, Kari Rioux, John D. Xavier, Ramnik J. Daly, Mark J. Barrett, J. de Lane, K. Edwards, C. Hart, A. Hawkey, C. Jostins, L. Kennedy, N. Lamb, C. Lee, J. Lees, C. Mansfield, J. Mathew, C. Mowatt, C. Newman, B. Nimmo, E. Parkes, M. Pollard, M. Prescott, N. Randall, J. Rice, D. Satsangi, J. Simmons, A. Tremelling, M. Uhlig, H. Wilson, D. Abraham, C. Achkar, J. P. Bitton, A. Boucher, G. Croitoru, K. Fleshner, P. Glas, J. Kugathasan, S. Limbergen, J. V. Milgrom, R. Proctor, D. Regueiro, M. Schumm, P. L. Sharma, Y. Stempak, J. M. Targan, S. R. Wang, M. H. |
| author_sort | Rivas, Manuel A. |
| collection | PubMed |
| description | Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(−7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. |
| format | Online Article Text |
| id | pubmed-4980482 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-49804822016-08-12 A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis Rivas, Manuel A. Graham, Daniel Sulem, Patrick Stevens, Christine Desch, A. Nicole Goyette, Philippe Gudbjartsson, Daniel Jonsdottir, Ingileif Thorsteinsdottir, Unnur Degenhardt, Frauke Mucha, Sören Kurki, Mitja I. Li, Dalin D'Amato, Mauro Annese, Vito Vermeire, Severine Weersma, Rinse K. Halfvarson, Jonas Paavola-Sakki, Paulina Lappalainen, Maarit Lek, Monkol Cummings, Beryl Tukiainen, Taru Haritunians, Talin Halme, Leena Koskinen, Lotta L. E. Ananthakrishnan, Ashwin N. Luo, Yang Heap, Graham A. Visschedijk, Marijn C. MacArthur, Daniel G. Neale, Benjamin M. Ahmad, Tariq Anderson, Carl A. Brant, Steven R. Duerr, Richard H. Silverberg, Mark S. Cho, Judy H Palotie, Aarno Saavalainen, Päivi Kontula, Kimmo Färkkilä, Martti McGovern, Dermot P. B. Franke, Andre Stefansson, Kari Rioux, John D. Xavier, Ramnik J. Daly, Mark J. Barrett, J. de Lane, K. Edwards, C. Hart, A. Hawkey, C. Jostins, L. Kennedy, N. Lamb, C. Lee, J. Lees, C. Mansfield, J. Mathew, C. Mowatt, C. Newman, B. Nimmo, E. Parkes, M. Pollard, M. Prescott, N. Randall, J. Rice, D. Satsangi, J. Simmons, A. Tremelling, M. Uhlig, H. Wilson, D. Abraham, C. Achkar, J. P. Bitton, A. Boucher, G. Croitoru, K. Fleshner, P. Glas, J. Kugathasan, S. Limbergen, J. V. Milgrom, R. Proctor, D. Regueiro, M. Schumm, P. L. Sharma, Y. Stempak, J. M. Targan, S. R. Wang, M. H. Nat Commun Article Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(−7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. Nature Publishing Group 2016-08-09 /pmc/articles/PMC4980482/ /pubmed/27503255 http://dx.doi.org/10.1038/ncomms12342 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| spellingShingle | Article Rivas, Manuel A. Graham, Daniel Sulem, Patrick Stevens, Christine Desch, A. Nicole Goyette, Philippe Gudbjartsson, Daniel Jonsdottir, Ingileif Thorsteinsdottir, Unnur Degenhardt, Frauke Mucha, Sören Kurki, Mitja I. Li, Dalin D'Amato, Mauro Annese, Vito Vermeire, Severine Weersma, Rinse K. Halfvarson, Jonas Paavola-Sakki, Paulina Lappalainen, Maarit Lek, Monkol Cummings, Beryl Tukiainen, Taru Haritunians, Talin Halme, Leena Koskinen, Lotta L. E. Ananthakrishnan, Ashwin N. Luo, Yang Heap, Graham A. Visschedijk, Marijn C. MacArthur, Daniel G. Neale, Benjamin M. Ahmad, Tariq Anderson, Carl A. Brant, Steven R. Duerr, Richard H. Silverberg, Mark S. Cho, Judy H Palotie, Aarno Saavalainen, Päivi Kontula, Kimmo Färkkilä, Martti McGovern, Dermot P. B. Franke, Andre Stefansson, Kari Rioux, John D. Xavier, Ramnik J. Daly, Mark J. Barrett, J. de Lane, K. Edwards, C. Hart, A. Hawkey, C. Jostins, L. Kennedy, N. Lamb, C. Lee, J. Lees, C. Mansfield, J. Mathew, C. Mowatt, C. Newman, B. Nimmo, E. Parkes, M. Pollard, M. Prescott, N. Randall, J. Rice, D. Satsangi, J. Simmons, A. Tremelling, M. Uhlig, H. Wilson, D. Abraham, C. Achkar, J. P. Bitton, A. Boucher, G. Croitoru, K. Fleshner, P. Glas, J. Kugathasan, S. Limbergen, J. V. Milgrom, R. Proctor, D. Regueiro, M. Schumm, P. L. Sharma, Y. Stempak, J. M. Targan, S. R. Wang, M. H. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title | A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title_full | A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title_fullStr | A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title_full_unstemmed | A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title_short | A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| title_sort | protein-truncating r179x variant in rnf186 confers protection against ulcerative colitis |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980482/ https://www.ncbi.nlm.nih.gov/pubmed/27503255 http://dx.doi.org/10.1038/ncomms12342 |
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proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT mathewc proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT mowattc proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT newmanb proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT nimmoe proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT parkesm proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT pollardm proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT prescottn proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT randallj proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT riced proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT satsangij proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT simmonsa proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT tremellingm proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT uhligh proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT wilsond proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT abrahamc proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT achkarjp proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT bittona proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT boucherg proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT croitoruk proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT fleshnerp proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT glasj proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT kugathasans proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT limbergenjv proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT milgromr proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT proctord proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT regueirom proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT schummpl proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT sharmay proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT stempakjm proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT targansr proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis AT wangmh proteintruncatingr179xvariantinrnf186confersprotectionagainstulcerativecolitis |