Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing

Pierre Klein, Martine Oloko, Fanny Roth, Valérie Montel, Alberto Malerba, Susan Jarmin, Teresa Gidaro, Linda Popplewell, Sophie Perie, Jean Lacau St Guily, Pierre De La Grange, Michael N. Antoniou, George Dickson, Gillian Butler-Browne, Bruno Bastide, Vincent Mouly, Capucine Trollet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)
159 Downloads (Pure)


A short abnormal polyalanine expansion in the polyadenylate-binding protein nuclear-1 (PABPN1) protein causes oculopharyngeal muscular dystrophy (OPMD). Mutated PABPN1 proteins accumulate as insoluble intranuclear aggregates in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice have been established, themolecular mechanisms which trigger pathological defects in OPMD and the role of aggregates remain to be determined. Using exon array, for the first time we have identified several splicing defects in OPMD. In particular, we have demonstrated a defect in the splicing regulation of the muscle-specific Troponin T3 (TNNT3) mutually exclusive exons 16 and 17 in OPMD samples compared to controls. This splicing defect is directly linked to the SC35 (SRSF2) splicing factor and to the presence of nuclear aggregates. As reported here, PABPN1 aggregates are able to trap TNNT3 pre-mRNA, driving it outside nuclear speckles, leading to an altered SC35-mediated splicing. This results in a decreased calcium sensitivity of muscle fibers,which could in turn plays a role inmuscle pathology. We thus report a novel mechanism of alternative splicing deregulation that may play a role in various other diseases with nuclear inclusions or foci containing an RNA binding protein.

Original languageEnglish
Pages (from-to)10929-10945
Number of pages17
JournalNucleic Acids Research
Issue number22
Early online date9 Aug 2016
Publication statusPublished - 1 Dec 2016


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