Dmd and beyond: molecular modifiers that alter disease progression in patients with dystrophinopathy

Abstract

Duchenne muscular dystrophy (DMD) is one of the most frequent and severe presentation of pediatric muscular dystrophies. There is great variability in the progression of the disease between DMD patients, even affected males with the same mutation lose the ability to walk at very different ages. Recent studies point to different SNPs in SPP1, LTBP4, CD40 and ACTN3 as the cause of these phenotypic variations. This work focused on characterizing these genetic modifiers in the DMD/DMB argentine cohort and validating their prognostic value. Of a total of 60 DMD patients, two groups of extreme phenotypes were created. The first contained 30 patients with loss of ambulation before the age of 11 (severe phenotype), while the second contained 24 patients who continue walking or who have lost ambulation at ages equal to or greater than 15 (mild phenotype). Previously reported SNPs in the SPP1, LTBP4, CD40 and ACTN3 genes were evaluated by PCR-Sanger sequencing. The chi square test was performed to determine that the differences between the severe and mild groups were significant. ACTN3 SNP showed a significant difference between both groups. The results of this work would indicate that the SNP rs1815739 in ACTN3 is a modifier for DMD progression, while the SNPs proposed in the other genes couldn´t be associated. The importance of the analysis of these molecular modifiers lies in understanding the origin of the variability of clinical manifestations among individuals affected with these monogenic disorders. This will allow, on the one hand, to improve the design and evaluation of clinical trials, as well as improve patient prognosis and personalization of treatments, opening the way to the development of new molecular targets for gene therapy.