Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening

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 3rd; David Boykin; Laura P W Ranum; John Douglas Cleary; Eric T Wang; J Andrew Berglund

doi:10.1016/j.isci.2022.104198

Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening

iScience. 2022 Apr 4;25(5):104198. doi: 10.1016/j.isci.2022.104198. eCollection 2022 May 20.

Authors

Jana R Jenquin^{1

2}, Alana P O'Brien³, Kiril Poukalov³, Yidan Lu³, Jesus A Frias^{2

4}, Hannah K Shorrock², Jared I Richardson^{1

2

4}, Hormoz Mazdiyasni², Hongfen Yang⁵, Robert W Huigens 3rd⁵, David Boykin⁶, Laura P W Ranum³, John Douglas Cleary², Eric T Wang³, J Andrew Berglund^{1

2

4}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
² RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222, USA.
³ Department of Molecular Genetics and Microbiology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
⁴ Department of Biological Sciences, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222, USA.
⁵ Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
⁶ Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

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.

Keywords: Biochemistry; Molecular physiology; Small molecule.

Abstract

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