Myotonic Dystrophy 2 (DM2) is a common muscular disease clinically related to Myotonic Dystrophy 1 (DM1). DM2 is caused by expansion of CCTG repeats in intron 1 of the zinc finger factor encoding gene, ZNF9, located on chromosome 3q. While some symptoms in the patients with DM1 and DM2 are similar, others are specific just for one type of disease. DM2 specific features include a lack of congenital form of disease, lack of developmental brain abnormalities, lack of retardation and significantly milder symptoms in skeletal muscle. The main focus of research in my laboratory is the investigation of molecular bases for DM1 and DM2. In the course of our studies on DM1, we found that expansion of CTG triplet repeats in DMPK gene causes DM1 pathology through un-translated RNA CUG repeats. CUG repeat expansion affects two RNA-binding proteins, CUGBP1 and MNBL. DM2 is also caused by expansion of untranslated CCTG repeats suggesting similar RNA-dependent mechanisms for DM1 and DM2. However, specific features of DM2 phenotype suggest that molecular mechanisms of DM2 are not identical to those of DM1. We found that RNA CCUG repeats in DM2 interact with distinct RNA-binding proteins and with large protein-protein complexes, designated as Mega Protein-Protein Complexes (MPPC). These complexes bind specifically to CCUG repeats but not to CUG repeats. MPPC are observed in cytoplasm and in nuclei of DM2 cells. The amounts of cytoplasmic MPPC are increased in DM2 myoblasts, while the levels of nuclear MPPC are reduced in DM2 patients. The major hypothesis of this application is that CCUG repeats cause DM2 pathology via changes of biological functions of large protein-protein complexes.
Three Specific Aims are designed to test this hypothesis. We have found that cytoplasmic MPPC contains 9 proteins including CUGBP1, eJF-2a and eIF-2p, all three proteins are involved in the regulation of translation of mRNAs.
Specific Aim 1 will identify other protein components of cytoplasmic MPPC and examine the role of cytoplasmic MPPC in mRNA translation.
Specific Aim 2 will determine identity of proteins within nuclear MPPC, examine if this complex plays a role in splicing and investigate if the alterations in nuclear MPPC cause abnormal splicing in DM2.
Specific Aim 3 will study the mechanisms by which expansion of CCUG repeats increases amounts of MPPC in cytoplasm of DM2 cells and reduces amounts of MPPC in nuclei.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lewis, Kyle; Valanejad, Leila; Cast, Ashley et al. (2017) RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner. Mol Cell Biol 37:
Jones, Karlie; Wei, Christina; Schoser, Benedikt et al. (2015) Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5. Proc Natl Acad Sci U S A 112:8041-5
Breaux, Meghan; Lewis, Kyle; Valanejad, Leila et al. (2015) p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways. Mol Cell Biol 35:3005-16
Hong, Il-Hwa; Lewis, Kyle; Iakova, Polina et al. (2014) Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments. J Biol Chem 289:1106-18
Bachinski, Linda L; Baggerly, Keith A; Neubauer, Valerie L et al. (2014) Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies. Neuromuscul Disord 24:227-40
de Haro, Maria; Al-Ramahi, Ismael; Jones, Karlie R et al. (2013) Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. PLoS Genet 9:e1003445
Meola, Giovanni; Jones, Karlie; Wei, Christina et al. (2013) Dysfunction of protein homeostasis in myotonic dystrophies. Histol Histopathol 28:1089-98
Timchenko, Lubov (2013) Molecular mechanisms of muscle atrophy in myotonic dystrophies. Int J Biochem Cell Biol 45:2280-7
Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A (2012) The role of CUGBP1 in age-dependent changes of liver functions. Ageing Res Rev 11:442-9
Jones, Karlie; Wei, Christina; Iakova, Polina et al. (2012) GSK3? mediates muscle pathology in myotonic dystrophy. J Clin Invest 122:4461-72

Showing the most recent 10 out of 22 publications