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

Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is caused by LAMA2 gene mutations, coding for laminin-211 (merosin) 2 subunit. LAMA2 mutations leading to complete laminin-211 absence result in an invariably severe clinical phenotype, with profound muscle weakness and respiratory insufficiency. Milder phenotypes are often associated with mutations allowing the production of a partially functional protein. While several dysregulated genes/pathways linked to LAMA2-RD muscle loss are known, an in-depth characterization of LAMA2-RD muscle gene expression profile in patients with mutations differentially affecting LAMA2 expression is lacking. We generated muscle transcriptomic data from patients with either complete or partial laminin-211 deficiency, and identified 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 were exclusively expressed in patients (and mice) completely lacking laminin-211, indicating aspects exacerbated in this cohort. Our work characterizes the main contributors of human LAMA2-RD pathology, providing insight into molecular pathways that could be used as disease biomarkers or as targets for therapeutic approaches.