Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1.

Alfonsina Ballester-Lopez,Ian Linares-Pardo,Jaume Coll-Cantí,Carles Puente Puente,Giuseppe Lucente,Emma Koehorst,Andrea Arbex,Gisela Nogales-Gadea,Alicia Martínez-Piñeiro,Darren G Monckton,Judit Núñez-Manchón,Sarah A Cumming,Guillem Pintos-Morell,Alejandro Lucia,Miriam Almendrote,Alba Ramos-Fransi

doi:10.3390/genes11111321

Abstract

Myotonic Dystrophy type 1 (DM1) is characterized by a high genetic and clinical variability. Determination of the genetic variability in DM1 might help to determine whether there is an association between CTG (Cytosine-Thymine-Guanine) expansion and the clinical manifestations of this condition. We studied the variability of the CTG expansion (progenitor, mode, and longest allele, respectively, and genetic instability) in three tissues (blood, muscle, and tissue) from eight patients with DM1. We also studied the association of genetic data with the patients’ clinical characteristics. Although genetic instability was confirmed in all the tissues that we studied, our results suggest that CTG expansion is larger in muscle and skin cells compared with peripheral blood leukocytes. While keeping in mind that more research is needed in larger cohorts, we have provided preliminary evidence suggesting that the estimated progenitor CTG size in muscle could be potentially used as an indicator of age of disease onset and muscle function impairment.

Highlights

Myotonic dystrophy type 1 (DM1) is caused by a CTG (Cytosine-Thymine-Guanine) expansion in the 30 untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene [1]
Size vs. mode allele, r = 0.900 (95% confidence interval 0.536–0.982); mode allele vs. longest allele, r = 0.805 (0.231–0.963); and longest allele vs. progenitor allele, r = 0.861 (0.398–0.975). These results suggested that the progenitor, the mode and the longest expansion size were uniformly distributed, with the CTG tract evenly expanded in blood
We further studied the relationship between genetic and clinical data and found a significant (p < 0.05) correlation between the progenitor allele found in muscle and both age of disease onset (r = −0.850 (−0.977–0.268)) and the Medical Research Council (MRC) corresponding to the studied muscles (r = −0.932 (−0.992–0.496))

Summary

Introduction

Myotonic dystrophy type 1 (DM1) is caused by a CTG (Cytosine-Thymine-Guanine) expansion in the 30 untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene [1]. The CTG expansion is highly unstable, showing size variation both within [2] and between tissues [3,4,5,6]. Genetic instability hinders the establishment of genotype/phenotype correlations in patients with DM1, and most studies assessing CTG expansion have focused solely on blood samples [7,8,9,10]. We used small pool polymerase chain reaction (SP-PCR) to study CTG expansion in three different tissues from affected patients. We estimated the progenitor allele, the mode of CTG expansion size and the highest. CTG repeat number, as well as the genetic instability of the CTG repeat (i.e., the difference between the progenitor and the mode CTG size) in the different tissues. We analyzed the potential association between the different CTG measures, on the one hand, and patients’ clinical phenotype, on the other

Methods

Results

Conclusion