Muscle transcriptome profiling reveals novel molecular pathways and biomarkers in laminin-α2 deficient patients.

Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is a neuromuscular disorder caused by mutations in the LAMA2 gene, coding for the α2 subunit of laminin-211 (merosin). LAMA2 mutations leading to complete laminin-211 absence result in a severe clinical phenotype with profound muscle weakness and respiratory insufficiency, whereas mutations allowing the production of a partially functional protein are often associated with milder phenotypes. While several dysregulated pathways linked to LAMA2-RD have been reported, an in-depth characterization of muscle gene expression in patients with mutations differentially affecting LAMA2 expression is still lacking. We generated muscle transcriptomic data from patients with either complete or partial laminin-211 deficiency alongside healthy controls, and relied on complementary bioinformatic tools and curated literature review to identify pathways linked to the most dysregulated processes. Genes related to fibrosis, inflammation and metabolism were similarly expressed in both patient cohorts. However, a subset of novel pro-fibrotic and pro-inflammatory genes and lncRNAs (including PF4 and HOTAIR) were exclusively expressed in patients (and mice) completely lacking laminin-211, indicating aspects exacerbated in this cohort. This study provides a comprehensive characterization of the main contributors to human LAMA2-RD pathology across disease severity, shedding light into novel genes and molecular pathways that could potentially serve as disease biomarkers or as targets for future therapeutic interventions.