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• W2883443744 abstract "Objective: To develop Multiplex Alternative Splice sequencing (MASseq) as a biomarker of therapeutic response in DM1. Background: Abnormal regulation of RNA alternative splicing is a hallmark of DM1. The mechanism is welldefined: toxic RNA from the DM1 gene interferes with the function of splicing regulatory factors (Muscleblind proteins). In DM1 mouse models, correction of splicing defects is predictive of therapeutic response. Design/Methods: We assessed muscle strength and obtained tibialis anterior (TA) muscle biopsies from DM1 patients (n=172) and healthy controls (HCs, n=25). We used multiplex RT-PCR followed by NGS to assess alternative splicing of 22 transcripts, including some that are linked to DM1 symptoms (e.g., chloride channel 1, insulin receptor). For each splice event, an alternative exon is either spliced in or skipped over in the mRNA. The sequencing data were used to calculate “percent spliced in” for each event. Overall splicing misregulation was then expressed as a composite alternative splicing (CAS) score encompassing all 22 splice events. Results were compared to DM1 mouse models. Results: As compared to conventional RNA sequencing, MASseq had ~10,000-fold greater efficiency for analyzing splicing defects, producing higher precision (10-fold narrower confidence limits) at lower cost. Alternative splicing was tightly regulated in HCs but severely misregulated in DM1 patients, resembling Muscleblind knockout mice. The CAS score in TA muscle correlated with weakness of ankle dorsiflexion, hand grip, and pinch (r ranging from 0.76 to 0.81, p Conclusions: MASseq is technically straightforward and enables high throughput analysis of splicing misregulation in DM1. Splicing defects in TA muscle correlate with weakness in distal muscles and show good test-retest reliability on repeat biopsies. Study Supported by: NIH/NINDS NS048843 (Wellstone Center), Muscular Dystrophy Association, Myotonic Dystrophy Foundation, Biogen Disclosure: Dr. Thornton has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Mankodi has nothing to disclose. Dr. Subramony has nothing to disclose. Dr. Ashizawa has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Statland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Strongbridge, Acceleron, Regeneron, and Sanofi. Dr. Arnold has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Myotonic Dystrophy Clinical Re has nothing to disclose." @default.
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• W2883443744 date "2018-04-10" @default.
• W2883443744 modified "2023-09-24" @default.
• W2883443744 title "Targeted Next Generation Sequencing (NGS) for Analysis of Splicing Biomarkers of Myotonic Dystrophy Type 1 (DM1) (S22.002)" @default.
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