Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening
Year: 2022
Type: article
Abstract: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are common forms of adult onset muscular dystrophy. Pathogenesis in both diseases is largely driven by production of toxic-expanded repeat RNAs that sequester MBNL RNA-binding proteins, causing mis-splicing. Given this shared pathogenesis, we hypothesized that diamidines, small molecules that rescue mis-splicing in DM1 models, could also rescue mis-splicing in DM2 models. While several DM1 cell models exist, few are available for DM2 limiting research and therapeutic development. Here, we characterize DM1 and DM2 patient-derived fibroblasts for use in small molecule screens and therapeutic studies. We identify mis-splicing events unique to DM2 fibroblasts and common events shared with DM1 fibroblasts. We show that diamidines can partially rescue molecular phenotypes in both DM1 and DM2 fibroblasts. This study demonstrates the potential of fibroblasts as models for DM1 and DM2, which will help meet an important need for well-characterized DM2 cell models.
Source: iScience
Authors: Jana R. Jenquin, Alana P. O’Brien, Kiril Poukalov, Yidan Lu, Jesus A. Frias, Hannah K. Shorrock, Jared I. Richardson, Hormoz Mazdiyasni, Hongfen Yang, Robert W. Huigens, David Boykin, Laura P.W. Ranum, John Douglas Cleary, Eric T. Wang, J. Andrew Berglund
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: G102572781, Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects, Molecular Genetic Characterization of SCA8, G6128049555, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Determining the factors that control dose-dependent splicing regulation by a master regulator, Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases
OpenAlex ID: W4224006550