Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12
| العنوان: | Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12 |
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| المؤلفون: | Romy L. S. Mesman, Marine Guillaud-Bataille, Mélanie Léoné, Capucine Delnatte, Aurélie Drouet, Alexandra Martins, Hélène Tubeuf, Laëtitia Meulemans, Omar Soukarieh, Pascaline Gaildrat, Violaine Bourdon, Nadia Boutry-Kryza, Sophie Krieger, Myriam Bronner, Fabienne Calléja, Johanna Sokolowska, Maud Privat, Dominique Stoppa-Lyonnet, Harry Vrieling, Maaike P.G. Vreeswijk, Françoise Révillion, Sandrine M. Caputo, Claude Houdayer, Sarab Lizard, Charlotte Grout, Françoise Bonnet-Dorion, Lisa Golmard, Virginie Caux-Moncoutier, Paul Vilquin, Virginie Guibert, Thierry Frebourg |
| المساهمون: | Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de Génétique Oncologique, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Institut Gustave Roussy (IGR), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Oncologie Génétique, de Prévention et Dépistage, Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Universiteit Leiden-Universiteit Leiden, Université de Lille-UNICANCER-Université de Lille-UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE), Centre hospitalier universitaire de Nantes (CHU Nantes), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de biochimie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP] |
| المصدر: | Cancer Research Cancer Research, American Association for Cancer Research, 2020, 80 (7), pp.1374-1386. ⟨10.1158/0008-5472.CAN-19-2491⟩ Cancer Research, 80(7), 1374-1386. AMER ASSOC CANCER RESEARCH Cancer Research, 2020, 80 (7), pp.1374-1386. ⟨10.1158/0008-5472.CAN-19-2491⟩ |
| بيانات النشر: | HAL CCSD, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetics, Cancer Research, media_common.quotation_subject, Nonsense, Alternative splicing, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, 3. Good health, 03 medical and health sciences, Exon, 030104 developmental biology, 0302 clinical medicine, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA splicing, splice, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Gene, media_common, Minigene |
| الوصف: | Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced BRCA2 exon 12 (E12) as a model system because its in-frame skipping leads to a potentially functional protein. All E12 variants corresponding to putative LoF variants or predicted to alter splicing (n = 40) were selected from human variation databases and characterized for their impact on splicing in minigene assays and, when available, in patient lymphoblastoid cell lines. Moreover, a selection of variants was analyzed in a mouse embryonic stem cell–based functional assay. Using these complementary approaches, we demonstrate that a subset of variants, including nonsense variants, induced in-frame E12 skipping through the modification of splice sites or regulatory elements and, consequently, led to an internally deleted but partially functional protein. These data provide evidence, for the first time in a cancer-predisposition gene, that certain presumed null variants can retain function due to their impact on splicing. Further studies are required to estimate cancer risk associated with these hypomorphic variants. More generally, our findings highlight the need to exercise caution in the interpretation of putative LoF variants susceptible to induce in-frame splicing modifications. Significance: This study presents evidence that certain presumed loss-of-function variants in a cancer predisposition gene can retain function due to their direct impact on RNA splicing. |
| اللغة: | English |
| تدمد: | 0008-5472 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-19-2491⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1ce592217bf40db2a0503c43fe1e3bb https://hal.uca.fr/hal-02929535 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a1ce592217bf40db2a0503c43fe1e3bb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00085472 15387445 |
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| DOI: | 10.1158/0008-5472.CAN-19-2491⟩ |