Abstract
Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to trans-dysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.
Highlights
Myotonic dystrophy type 1Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide repeat disorder, caused by an expanded CTG repeat in the 3’ UTR of the dystrophia myotonica protein kinase (DMPK) gene [1]
We propose that the model can serve as a valuable tool in evaluating efficacy of any treatment for DM1 as such treatment enters pre-clinical or clinical trials, by enabling investigators to directly quantify the treatment effect as measured by effective reduction of DM1 CTG repeat length rather than assessing the shift in alternative splicing (AS) of any one transcript
Using our predictive model based on Partial Least Squares Regression (PLSR) and a selection of candidate biomarkers: DM1-AS; DM1-alternative polyadenylation (APA); TNNI1 and ALL, we can report the following capabilities to predict MAL from mRNA profiles
Summary
Myotonic dystrophy type 1Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide repeat disorder, caused by an expanded CTG repeat in the 3’ UTR of the dystrophia myotonica protein kinase (DMPK) gene [1]. The pathomechanism of the dysregulation of splicing factor MBNL1 is perhaps best understood, with MBNL1 sequestration to the toxic DMPK RNA product resulting in alternative splicing defects of pre-mRNAs of multiple genes, including the chloride channel (CLCN1), brain microtubule-associated tau (MAPT) and insulin receptor (INSR) [4]. Such alternative splicing (AS) defects are generally believed to be a major contributing factor of clinical symptoms of DM1, such as myotonia (CLCN1) or abnormal glucose response (INSR), and have been postulated to play a role in cardiac conduction defects (RYR2, SERCA2, TNNT2) [5]. The severity of symptoms is positively correlated with CTG repeat length [2]
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