Research projects

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders that primarily affect skeletal muscle and are characterized by progressive weakness and atrophy of the pelvic and shoulder girdle muscles. Their clinical and histopathological characteristics frequently overlap with other neuromuscular dystrophies. Our goal was to identify, by a non-invasive method, a molecular signature including biochemical and epigenetic parameters with clinical potential value.  

First of all, the exomes of LGMD-diagnosed patients were sequenced and mutations were found in TTN, TNPO3, CAPN3 or SGCA genes that would directly explain the appearance of LGMD. On the other hand, whole miRNome sequencing of serum samples from 6 LGMD patients and their matched-controls was used to identify a specific signature of the disease. Most of differentially expressed miRs in LGMD patients were up-regulated whilst only three of sequenced miRs were significantly down-regulated when compared to controls. Bioinformatic analysis of target genes revealed cell cycle, muscle tissue development, regeneration and senescence as the most affected pathways. To further confirm these results, the levels of four deregulated miRs (miR-122-5p, miR-192-5p, miR-19b-3p and miR-323b-3p), together with the myomiR miR-206, were validated by qPCR in LGMD and Duchenne’s (DMD) and facioscapulohumeral (FSHD) muscular dystrophies. ROC curves (ROC) revealed high AUC values for selected miRs in all groups, indicating that these miRs have good sensitivity and specificity to distinguish LGMD, DMD and FSHD patients from healthy controls. Additionally, biochemical and clinical parameters were analysed, and a strong correlation between miRs and biochemical data was only found in LGMD patients: miR-192-5p and miR-122-5p negatively correlated with CK, while miR-192-5p positively correlated with vitamin D3 and ALP.

All in all, we propose here a specific combination of easy-to-obtain molecular and biochemical parameters with potential value for diagnosis/prognosis of LGMD patients versus the most frequent neuromuscular dystrophies DMD and FSHD.