rna splicing is responsive to mbnl1 doserna剪接是mbnl1剂量响应.pdfVIP

RNA Splicing Is Responsive to MBNL1 Dose 1 1¤ 1¤ 1 2 1 Sonali P. Jog , Sharan Paul , Warunee Dansithong , Stephanie Tring , Lucio Comai *, Sita Reddy * 1 Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, University of Southern California, Los Angeles, California, United States of America, 2 Department Molecular Microbiology and Immunology, Institute for Genetic Medicine, University of Southern California, Los Angeles, California, United States of America Abstract Myotonic dystrophy (DM1) is a highly variable, multi-system disorder resulting from the expansion of an untranslated CTG tract in DMPK. In DM1 expanded CUG repeat RNAs form hairpin secondary structures that bind and aberrantly sequester the RNA splice regulator, MBNL1. RNA splice defects resulting as a consequence of MBNL1 depletion have been shown to play a key role in the development of DM1 pathology. In patient populations, both the number and severity of DM1 symptoms increase broadly as a function of CTG tract length. However significant variability in the DM1 phenotype is observed in patients encoding similar CTG repeat numbers. Here we demonstrate that a gradual decrease in MBNL1 levels results both in the expansion of the repertoire of splice defects and an increase in the severity of the splice alterations. Thus, MBNL1 loss does not have an all or none outcome but rather shows a graded effect on the number and severity of the ensuing splice defects. Our results suggest that once a critical threshold is reached, relatively small dose variations of free MBNL1 levels, which may reflect modest changes in the size of the CUG tract or the extent of hairpin secondary structure formation, can significant