Disease and therapeutic mechanisms in collagen XIII-dependent myasthenias

Collagen XIII is a postsynaptic membrane protein of the neuromuscular junction (NMJ). In humans, COL13A1 mutations cause congenital myasthenic syndrome type 19 (CMS19), leading to muscle weakness and severe respiratory difficulties from birth. Collagen XIII is required for NMJ morphology, maturation, and function, but its role in neuromuscular development remains unclear. Without collagen XIII, motor axons locally sprouted beyond acetylcholine receptor (AChR) clusters, suggesting compromised motor synapse establishment. NMJ defects affect slow-to-fast twitch transition by adulthood, and RNA sequencing was performed on slow-twitch soleus muscle to identify affected pathways.

Transcript levels of differentially expressed genes (DEGs) in wild-type and collagen XIII knock-out mice were confirmed by RT-qPCR and comparison with denervation data sets. Mdga1, coding for MAM Domain-Containing Glycosylphosphatidylinositol Anchor Protein 1 involved in axon guidance, showed increased expression in knock-out mice. In vitro assays confirmed collagen XIII-MDGA1 binding, while staining showed mis-location of MDGA1 in knock-out mice. Studies indicate that collagen XIII acts as a motor axon growth stop signal through transsynaptic adhesion or AChR cluster organization, contributing to muscle integrity via the NMJ.

CMS19 is severe during the early years, after which NMJ defects stabilize without progression. Acetylcholine esterase (AChE) inhibition treatment isn't always effective, while salbutamol benefits patients. Salbutamol effects were studied in myasthenic collagen XIII knock-out mice with daily injections from 5 weeks of age for four and seven weeks. Treatment benefits were verified through muscle strength, NMJ morphology and gene expression, revealing therapeutic potential in CMS19 and collagen XIII-dependent myasthenia gravis.