Previtali, S. C. | Search bioRxiv

bioRxiv2025

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.

neuroscience↗

bioRxiv2022

Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dyW/dyW mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and LNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dyW/dyW mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy3K/dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-2 in many, if not all tissues affected in LAMA2 MD.

neuroscience↗