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ABSTRACT
In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies.
Abbreviations
| 3′UTR | = | 3′ untranslated region |
| ACCN3 | = | Amiloride-sensitive cation channel 3 |
| ASE | = | alternative splicing events |
| bp | = | base-pair |
| CACNA1d | = | Calcium Channel, Voltage-Dependent, L Type, Alpha 1D Subunit |
| CLCN2 | = | Chloride channel 2 |
| CLCN6 | = | Chloride channel 6 |
| DM1 | = | Myotonic Dystrophy Type I |
| DMD | = | Duchenne Muscular Dystrophy |
| DMPK | = | dystrophia myotonica protein kinase |
| DNA-PK | = | DNA-dependent protein kinase |
| FHL3 | = | Four And A Half LIM Domains 3 |
| FN1 | = | Fibronectin 1 |
| G6PC3 | = | Glucose 6 Phosphatase Catalytic 3 |
| HIF1α | = | Hypoxia-inducible factor 1-α |
| hnRNP A2B1 | = | Heterogeneous Nuclear Ribonucleoprotein A2/B1 |
| INSR | = | Insulin Receptor |
| IRAlus | = | Inverted Repeat Alus |
| ISS | = | Intronic Splicing Silencers |
| KCNMA1 | = | Potassium Channel, Calcium Activated Large Conductance Subfamily M Alpha, Member 1 |
| LRRC23 | = | Leucine Rich Repeat Containing 23 |
| LTBP4 | = | Latent Transforming Growth Factor-β Binding Protein 4 |
| MBNL1 | = | Muscleblind-Like 1 |
| MFE | = | minimum free energy |
| NLS | = | nuclear localization signal |
| NRG1 | = | Neuregulin 1 |
| PRPF8 | = | Pre-mRNA Processing Factor 8 |
| PSI | = | Percent splicing index |
| RAN translation | = | Repeat-associated non-ATG translation |
| RBDs | = | RNA-binding domains |
| RBPs | = | RNA-binding proteins |
| SBSs | = | Stau1-binding-sites |
| SF3B1 | = | Splicing Factor 3b, Subunit 1 |
| SF3B2 | = | Splicing Factor 3b, Subunit 2 |
| SFRS1 | = | Serine/arginine-rich splicing factor 1 |
| SMA | = | Spinal Muscular Atrophy |
| Stau1 | = | Staufen1 |
| Stau2 | = | Staufen2 |
| TBPH | = | TAR DNA-binding protein-43 homolog |
| TGFβ | = | Transforming Growth Factor Beta |
| TNNT2 | = | cardiac Troponin T |
| U2AF65 | = | U2 snRNP auxiliary factor 65-kDa subunit |
| WT | = | wild-type. |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors would like to thank Roscoe Klinck and Benoit Chabot for carrying out the high-throughput RT-PCR splicing screen and help with the analysis, Lynda Rocheleau and Martin Pelchat for performing the identification and mapping of Alu elements on ASEs, Nicholas J. G. Webster for the generous donation of the IR-minigenes and finally, Guy Bélanger for technical assistance.
Funding
This work was funded by grants from the Muscular Dystrophy Association (294865), Association Française contre les Myopathies (18285), Canadian Institutes of Health Research (The Institute of Musculoskeletal Health and Arthritis) via the Canadian Muscular Dystrophy Association and the Rachel Fund for Myotonic Dystrophy, and supported by The University of Ottawa Brain and Mind Research Institute Center for Neuromuscular Disease - Scholarships in Translational Research Award and The Queen Elizabeth II Graduate Scholarships in Science & Technology Award. Jocelyn Côté was the recipient of a Canada Research Chair (Tier II) in RNA Metabolism funded through CIHR.