0 avis
Phenotypic and genomic characterization of Becker dystrophy patients with 45 to 55 exons deletion
Archive ouverte
Edité par CCSD -
International audience. Becker muscular dystrophy (BMD) is an X linked disorder with 1/30000 life births incidence and is characterized by a progressive muscular dystrophy with or without cardiomyopathy. We present a population of 49 BMD patients with a DMD gene in-phase deletion of exons 45 to 55 (BMDdel45-55). Interestingly, emerging regulatory actors as lncRNA are localized in introns 44 and 55 (Bovolenta et al., 2012). Thus, the specific neo-introns of each patient could create or modify the lncRNA and/or RNA non-coding sequences. The objective of this study is to identify modifier factors involved in phenotypic variability in BMDdel45-55 patients. As described in literature, 63% of Duchenne patients are eligible to a multiexon skipping therapy by skipping exons 45 to 55.We performed (i) a phenotypic characterization of 49 patients, (ii) a lncRNA profile in 40/49patients and (iii) a WGS in 19/49patients. We have established the profile of lncRNA presence at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52).In our cohort 22% of patients have dilatative cardiomyopathy, interestingly in 51% the first signs age was <18 y.o. After the cardiac involvement, the most disabling complains are the walking/running difficulties (46 %) and fatigue (34%). With the exception of one outlier there is a strong correlation between the age of the first signs and the presence of cardiomyopathy. We have established lncRNA profile in 38/49 patients. The cluster with the less numbers of lncRNA have a “milder” phenotype. In addition, in Myo-45-52 the profile of lncRNA expression investigated by RT-PCR, underlined two lacking lncRNA.This study allowed us to describe phenotypic and genomic profile in the largest reported cohort of BMDdel45-55 patients. We identified a cluster with the less numbers of lncRNA with a “milder” phenotype. Genomic data profiling of the candidates for multiexon skipping therapy of 45 to 55 exons would have a favorable contribution in the design of these therapeutic approaches.Bovolenta, M., Erriquez, D., Valli, E., Brioschi, S., Scotton, C., Neri, M., Falzarano, M.S., Gherardi, S., Fabris, M., Rimessi, P., et al. (2012). The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms. PloS One 7, e45328.
Consulter en ligne
Suggestions
Du même auteur
