Over-expression of Microspan, a novel component of the sarcoplasmic reticulum, causes severe muscle pathology with triad abnormalities

Sarcospan (SSPN) is a core component of the dystrophin-glycoprotein complex (DGC). Multiple SSPN transcripts are ubiquitously expressed and SSPN splicing is disrupted in many lung tumors, suggesting the importance of SSPN-related mRNAs. We describe the isolation of an alternatively spliced isoform of SSPN, which we designate 'microspan' based on its small size relative to SSPN. Microspan has two transmembrane domains and a novel C-terminus. We demonstrate that microspan is not an integral component of the DGC and is not perturbed by the loss of dystrophin. Microspan protein is detected at the sarcoplasmic reticulum (SR) using indirect immunofluorescence and immunoelectron microscopy. Furthermore, microspan purifies with skeletal muscle SR membranes and not transverse tubules. Mice engineered to over-express microspan display severe kyphosis and die at approximately 8 weeks of age. Levels of ryanodine receptor, dihydropyridine receptor, and SERCA-1 are greatly reduced in microspan transgenic muscle. Furthermore, electron microscopy reveals that microspan over-expression causes a dramatic perturbation in triad structure. Our findings suggest that microspan is an important component of the SR and may contribute to excitation-contraction coupling.