Analysis of miRNA rare variants in Amyotrophic Lateral Sclerosis and in silico prediction of their biological effects

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors. Among the genetic risk factors, the contribution of non-coding elements, such as microRNAs (miRNAs), to ALS disease susceptibility remains largely unexplored. This work aims to identify rare variants in miRNA genes in sporadic ALS (sALS) patients which may cause a defective miRNA maturation or altered target gene recognition by changing miRNA secondary structure or seed sequence, respectively. We here developed a workflow to study miRNA rare variants from WGS data and to predict their biological effects on miRNA folding, maturation and target gene recognition. Although this in silico approach certainly needs functional validation in vitro and in vivo, it may help define the role of miRNA variability in ALS and complex diseases.