Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation
2010; Wiley; Volume: 31; Issue: 3 Linguagem: Inglês
10.1002/humu.21187
ISSN1098-1004
AutoresTomoko Kobayashi, Yoko Aoki, Tetsuya Niihori, Hélène Cavé, Alain Verloès, Nobuhiko Okamoto, Hiroshi Kawame, Ikuma Fujiwara, Fumio Takada, Takako Ohata, Satoru Sakazume, Tatsuya Ando, Noriko Nakagawa, Pablo Lapunzina, Antonio González Meneses, Gabriele Gillessen‐Kaesbach, Dagmar Wieczorek, Kenji Kurosawa, Seiji Mizuno, Hirofumi Ohashi, Albert David, Nicole Philip, Afag Guliyeva, Yoko Narumi, Shigeo Kure, Shigeru Tsuchiya, Yoichi Matsubara,
Tópico(s)Galectins and Cancer Biology
ResumoHuman MutationVolume 31, Issue 3 p. 284-294 Research Article Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation† Tomoko Kobayashi, Tomoko Kobayashi Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoko Aoki, Corresponding Author Yoko Aoki aokiy@mail.tains.tohoku.ac.jp Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanDepartment of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, JapanSearch for more papers by this authorTetsuya Niihori, Tetsuya Niihori Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorHélène Cavé, Hélène Cavé APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, FranceSearch for more papers by this authorNobuhiko Okamoto, Nobuhiko Okamoto Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, JapanSearch for more papers by this authorHiroshi Kawame, Hiroshi Kawame Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan Department of Genetic Counseling, Ochanomizu University, Tokyo, JapanSearch for more papers by this authorIkuma Fujiwara, Ikuma Fujiwara Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorFumio Takada, Fumio Takada Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, JapanSearch for more papers by this authorTakako Ohata, Takako Ohata Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, JapanSearch for more papers by this authorSatoru Sakazume, Satoru Sakazume Division of Medical Genetics, Gunma Children's Medical Center, Gunma, JapanSearch for more papers by this authorTatsuya Ando, Tatsuya Ando Department of Pediatrics, Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this authorNoriko Nakagawa, Noriko Nakagawa Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorPablo Lapunzina, Pablo Lapunzina Servicio de Genetica Medica, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorAntonio G. Meneses, Antonio G. Meneses Servicio de Genetica Medica, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorGabriele Gillessen-Kaesbach, Gabriele Gillessen-Kaesbach Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, GermanySearch for more papers by this authorDagmar Wieczorek, Dagmar Wieczorek Institut für Humangenetik, Universitaetsklinikum Essen Universitaet Duisburg-Essen, Essen, GermanySearch for more papers by this authorKenji Kurosawa, Kenji Kurosawa Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, JapanSearch for more papers by this authorSeiji Mizuno, Seiji Mizuno Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, JapanSearch for more papers by this authorHirofumi Ohashi, Hirofumi Ohashi Division of Medical Genetics, Saitama Children's Medical Center, Saitama, JapanSearch for more papers by this authorAlbert David, Albert David CHU Nantes, Nantes, FranceSearch for more papers by this authorNicole Philip, Nicole Philip Hôpital de la Timone, Marseille, FranceSearch for more papers by this authorAfag Guliyeva, Afag Guliyeva Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoko Narumi, Yoko Narumi Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorShigeo Kure, Shigeo Kure Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorShigeru Tsuchiya, Shigeru Tsuchiya Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoichi Matsubara, Yoichi Matsubara Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this author Tomoko Kobayashi, Tomoko Kobayashi Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoko Aoki, Corresponding Author Yoko Aoki aokiy@mail.tains.tohoku.ac.jp Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanDepartment of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, JapanSearch for more papers by this authorTetsuya Niihori, Tetsuya Niihori Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorHélène Cavé, Hélène Cavé APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, FranceSearch for more papers by this authorNobuhiko Okamoto, Nobuhiko Okamoto Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, JapanSearch for more papers by this authorHiroshi Kawame, Hiroshi Kawame Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan Department of Genetic Counseling, Ochanomizu University, Tokyo, JapanSearch for more papers by this authorIkuma Fujiwara, Ikuma Fujiwara Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorFumio Takada, Fumio Takada Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, JapanSearch for more papers by this authorTakako Ohata, Takako Ohata Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, JapanSearch for more papers by this authorSatoru Sakazume, Satoru Sakazume Division of Medical Genetics, Gunma Children's Medical Center, Gunma, JapanSearch for more papers by this authorTatsuya Ando, Tatsuya Ando Department of Pediatrics, Jikei University School of Medicine, Tokyo, JapanSearch for more papers by this authorNoriko Nakagawa, Noriko Nakagawa Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorPablo Lapunzina, Pablo Lapunzina Servicio de Genetica Medica, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorAntonio G. Meneses, Antonio G. Meneses Servicio de Genetica Medica, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorGabriele Gillessen-Kaesbach, Gabriele Gillessen-Kaesbach Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, GermanySearch for more papers by this authorDagmar Wieczorek, Dagmar Wieczorek Institut für Humangenetik, Universitaetsklinikum Essen Universitaet Duisburg-Essen, Essen, GermanySearch for more papers by this authorKenji Kurosawa, Kenji Kurosawa Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, JapanSearch for more papers by this authorSeiji Mizuno, Seiji Mizuno Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, JapanSearch for more papers by this authorHirofumi Ohashi, Hirofumi Ohashi Division of Medical Genetics, Saitama Children's Medical Center, Saitama, JapanSearch for more papers by this authorAlbert David, Albert David CHU Nantes, Nantes, FranceSearch for more papers by this authorNicole Philip, Nicole Philip Hôpital de la Timone, Marseille, FranceSearch for more papers by this authorAfag Guliyeva, Afag Guliyeva Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoko Narumi, Yoko Narumi Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorShigeo Kure, Shigeo Kure Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorShigeru Tsuchiya, Shigeru Tsuchiya Department of Pediatrics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this authorYoichi Matsubara, Yoichi Matsubara Department of Medical Genetics, Tohoku University School of Medicine, Sendai, JapanSearch for more papers by this author First published: 05 January 2010 https://doi.org/10.1002/humu.21187Citations: 75 † Communicated by Nancy B. Spinner AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Noonan syndrome (NS) and related disorders are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. The dysregulation of the RAS/MAPK pathway appears to be a common molecular pathogenesis of these disorders: mutations in PTPN11, KRAS, and SOS1 have been identified in patients with NS, those in KRAS, BRAF, MAP2K1, and MAP2K2 in patients with CFC syndrome, and those in HRAS mutations in Costello syndrome patients. Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In the current study, we identified eight RAF1 mutations in 18 of 119 patients with NS and related conditions without mutations in known genes. We summarized clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported. Hypertrophic cardiomyopathy and short stature were found to be more frequently observed in patients with RAF1 mutations. Mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (serine at position 259; S259). Functional studies revealed that the RAF1 mutants located in the CR2 domain resulted in the decreased phosphorylation of S259, and that mutant RAF1 then dissociated from 14-3-3, leading to a partial ERK activation. Our results suggest that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK. Hum Mutat 30:1–11, 2010. © 2010 Wiley-Liss, Inc. Citing Literature Supporting Information Additional Supporting information may be found in the online version of this article Filename Description humu_21187_sm_SupplInfo1.pdf205 KB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume31, Issue3March 2010Pages 284-294 RelatedInformation
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