Mutations of the selenoprotein N gene (SEPN1) cause SEPN1‐related myopathy (SEPN1‐RM), a novel early‐onset muscle disorder formerly divided into four different nosological categories. Selenoprotein N (SelN) is the only selenoprotein involved in a genetic disease; its function being unknown, no treatment is available for this potentially lethal disorder. Our objective was to clarify the role of SelN and the pathophysiology of SEPN1‐RM to identify therapeutic targets.

We established and analyzed an ex vivo model of SelN deficiency using fibroblast and myoblast primary cultures from patients with null SEPN1 mutations. DCFH assay, OxyBlot, Western blot, Fura‐2, and cell survival studies were performed to measure intracellular oxidant activity, oxidative stress markers, calcium handling, and response to exogenous treatments.

SelN‐depleted cells showed oxidative/nitrosative stress manifested by increased intracellular oxidant activity (reactive oxygen species and nitric oxide) and/or excessive oxidation of proteins, including the contractile proteins actin and myosin heavy chain II in myotubes. SelN‐devoid myotubes showed also Ca²⁺ homeostasis abnormalities suggesting dysfunction of the redox‐sensor Ca²⁺ channel ryanodine receptor type 1. Furthermore, absence of SelN was associated with abnormal susceptibility to H₂O₂‐induced oxidative stress, demonstrated by increased cell death. This cell phenotype was restored by pretreatment with the antioxidant N‐acetylcysteine.

SelN plays a key role in redox homeostasis and human cell protection against oxidative stress. Oxidative/nitrosative stress is a primary pathogenic mechanism in SEPN1‐RM, which can be effectively targeted ex vivo by antioxidants. These findings pave the way to SEPN1‐RM treatment, which would represent a first specific pharmacological treatment for a congenital myopathy. Ann Neurol 2009;65:677–686