Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention

Abstract

Background: Duchenne Muscular Dystrophy (DMD) is a progressive, fatal neuromuscular disorder caused by mutations in the DMD gene. Emerging antisense oligomer based exon skipping therapy provides hope for the restoration of the reading frame. Objectives: Population-based DMD mutation database may enable exon skipping to be used for the benefit of patients. Hence, we planned this study to identify DMD gene variants in North Indian DMD cases. Methods: A total of 100 DMD cases were recruited and Multiplex ligation-dependent probe amplification (MLPA) analysis was performed to obtain the deletion and duplication profile. Results: Copy number variations (deletion/duplication) were found in 80.85% of unrelated DMD cases. Sixty-eight percent of cases were found to have variations in the distal hotspot region (Exon 45- 55) of the DMD gene. Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/ multiple exon variations. As per Leiden databases, 86.84% cases harboured out-of-frame mutations. Domain wise investigation revealed that 68% of mutations were localized in the region of spectrin repeats. Dp140 isoform was predicted to be absent in 62/76 (81.57%) cases. A total of 45/80 (56.25 %) and 23/80 (28.70%) DMD subjects were predicted to be amenable to exon 51 and exon 45 skipping trials, respectively. Conclusion: A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population.

Computational cognitive modeling and validation of Dp140 induced alteration of working memory in Duchenne Muscular Dystrophy

“…The number of Dp140 − ve and Dp140 + ve cases varied in our cohort resulting in the group size difference. This differences have also been reported in earlier studies 30 .…”

“…A total of 84 DMD cases with > 6 years of age, were subjected to MLPA based screening of copy number variations (CNVs). Spectrum of CNVs in our DMD cohort has been reported previously 30 . MLPA analysis revealed CNVs i.e.…”

The Role of Dystrophin Gene Mutations in Neuropsychological Domains of DMD Boys: A Longitudinal Study

“…Genetic diagnosis was carried out by Multiplex Ligation Dependent Probe Amplification (MLPA) as described previously. 19,20 IQ: Malin's intelligence scale for Indian Children (MISIC), an adaptation to Wechsler intelligence scale for children (WISC), was employed to assess the IQ. Briefly, verbaland performance-based IQs (VIQ and PIQ) were derived to finally form the IQ.…”

“…Genetic diagnosis was carried out by Multiplex Ligation Dependent Probe Amplification (MLPA) as described previously. 19 , 20 …”

Working Memory Alterations Plays an Essential Role in Developing Global Neuropsychological Impairment in Duchenne Muscular Dystrophy

“…The study was conducted in the Neuroscience Research Lab of Postgraduate Institute of Medical Education and Research, Chandigarh, India. The pathogenic variants in the DMD gene were obtained by multiplex ligation-dependent probe amplification as described earlier in our cohort ( Tyagi et al, 2019a ).…”