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Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12

Laëtitia Meulemans 1 Romy L.S. Mesman 2 Sandrine Caputo 3, 4 Sophie Krieger 1 Marine Guillaud-Bataille 5 Virginie Caux-Moncoutier 3, 4 Mélanie Léoné 6 Nadia Boutry-Kryza 7 Johanna Sokolowska 8 Françoise Révillion 9 Capucine Delnatte 10 Hélène Tubeuf 1 Omar Soukarieh 1 Francoise Bonnet-Dorion 11 Virginie Guibert 10 Myriam Bronner 12, 8 Violaine Bourdon 13 Sarab Lizard 8 Paul Vilquin 14 Maud Privat 15, 16 Aurélie Drouet 1 Charlotte Grout 1 Fabienne M.G.R. Calléja 2 Lisa Golmard 3, 4 Harry Vrieling 2 Dominique Stoppa-Lyonnet 3, 17 Claude Houdayer 1, 3, 18 Thierry Frebourg 1, 18 Maaike P.G. Vreeswijk 2 Alexandra Martins 1 Pascaline Gaildrat 1 
Abstract : 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.
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Submitted on : Thursday, September 3, 2020 - 3:13:26 PM
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Laëtitia Meulemans, Romy L.S. Mesman, Sandrine Caputo, Sophie Krieger, Marine Guillaud-Bataille, et al.. Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12. Cancer Research, American Association for Cancer Research, 2020, 80 (7), pp.1374-1386. ⟨10.1158/0008-5472.CAN-19-2491⟩. ⟨hal-02929535⟩



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