Relatively low levels of SSPN protein expression (10-fold over endogenous levels) resulted in severe toxicity. This is Fig. 10. Schematic diagram showing a pathogenetic mechanism for SSPN-mediated disruption of the DGC. The **data** in the current report support a model of SSPNinduced dysfunction of the DGC. We propose that SSPN (green) overexpression at the sarcolemma (1) causes clustering of the SGs (yellow) into insoluble aggregates (2). Perturbation of the SG-SSPN subcomplex within the DGC impairs its ability to properly anchor ␣-DG (red) at the sarcolemma (3). The destabilization of ␣-DG attachment to the sarcolemma leads to perturbation of basement membrane (blue) assembly (4). It is feasible that disruption of the basement membrane leads to aberrant cellular signaling (5), which may be responsible for the increased levels of apoptosis in phenotypic SSPN-Tg mice. By this pathogenetic mechanism, SSPN disrupts protein interactions within and across the membrane bilayer leading to a severe phenotype that is reminiscent of congenital MD.