NMJ-associated transcriptomic remodeling correlates with disease severity in juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease primarily affecting children, with a female predominance. While muscle fiber inflammation has been extensively investigated, the contribution of the neuromuscular junction (NMJ) and its cellular microenvironment to JDM pathogenesis remains poorly understood. This study aimed to characterize NMJ-related gene expression patterns in JDM to identify potential pathogenic mechanisms and candidate biomarkers.

An integrated transcriptomic analysis was conducted using two publicly available microarray datasets comprising 40 JDM patients and 22 healthy controls. Twenty-one genes representing five major NMJ functional categories were analyzed: cholinergic transmission, nicotinic acetylcholine receptors, extracellular matrix components, glial markers, and postsynaptic signaling molecules. Differential expression, discriminatory performance, correlation, clustering, and tissue deconvolution analyses were performed.

Eighteen of the 21 NMJ-related genes were significantly differentially expressed in JDM (FDR-adjusted p < 0.05). Among these, MBP showed the most pronounced dysregulation and high discriminatory performance (AUC = 0.976, p = 6.10 × 10^-16), with marked downregulation associated with increased muscle weakness. Other genes also demonstrated strong discriminatory performance, including AGRN (AUC = 0.941), NID1 (AUC = 0.932), CHRNA1 (AUC = 0.927), NRXN3 (AUC = 0.916), and RYR1 (AUC = 0.913). Correlation analyses revealed disruption of physiological co-expression patterns and the emergence of disease-specific interactions, including altered associations between glial markers and cholinergic components. CHRNA1 expression correlated with both muscle and skin disease activity scores, whereas GFAP expression was associated with disease duration. Clustering analysis indicated a reorganization of NMJ-related gene networks in JDM. Tissue deconvolution suggested that CHRNA1 expression may reflect a shift from inflammatory cell infiltration toward preservation of muscle cell identity.

These findings reveal widespread NMJ-associated transcriptomic remodeling in JDM, involving synaptic, cholinergic, and neuroglial components. The identification of candidate transcriptional biomarkers, particularly MBP and CHRNA1, which show association with disease activity, may warrant further evaluation as potential monitoring tools in independent cohorts. Overall, this study supports a role for NMJ-associated transcriptomic remodeling in JDM pathophysiology and suggests new avenues for mechanistic investigation.