LAMA2-related muscular dystrophy (LAMA2-RD), a congenital muscular dystrophy that affects an estimated 1 in 120,000 live births, is a multisystem disease characterized not only by muscle degeneration but also by abnormal peripheral nerve myelination. The latter phenotype is thought to result from defects in the initial establishment of myelin. However, the natural history of this abnormal myelination and the impact of loss of LAMA2 on downstream pathways in the peripheral nerve over time remain unexplored.
In this study, we utilized a hypomorphic mouse model with a normal lifespan to assess morphological and transcriptional changes in LAMA2-RD peripheral nerves at mid and late disease stages which have not been previously explored. Using a combination of light and transmission electron microscopy, we found that loss of LAMA2 results in amyelinated patches in the sciatic nerve, which seem to progressively enlarge over time, suggesting that LAMA2 is necessary not only for initial myelin formation but also for its maintenance. Additionally, we observed increased myelin infolding, a phenotype reminiscent of B4-integrin loss. Analysis of the most perturbed cellular pathways using RNA sequencing identified downregulation of multiple genes involved in calcium signaling. Correspondingly, primary Schwann cells isolated from LAMA2-RD mice exhibited reduced intracellular calcium levels compared to wildtype control. Overall, our studies demonstrate that LAMA2 is necessary for both the initiation and maintenance of myelination, with perturbations in calcium signaling potentially contributing to disease etiology. This work identifies calcium signaling as a novel potential therapeutic target to improve peripheral nerve myelination in LAMA2-RD.