Wild-type and missense mutants of retinoschisin co-assemble resulting in either intracellular retention or incorrect assembly of the functionally active octamer.

The X-linked disease retinoschisis is caused by mutations in the RS1 gene encoding retinoschisin, most commonly missense mutations leading to a lack of secretion of functional protein. One potential approach to treat this disease would be the introduction of the wild-type protein by gene therapy in affected individuals. Retinoschisin normally forms homo-octamers, so co-expression of the wild-type protein with the mutant could result in their co-assembly. In the present study, we show that retinoschisin assembles into an octamer before transport from the endoplasmic reticulum and that co-assembly of wild-type and mutant protein can occur when they are co-expressed in the same cell. This co-assembly results in the retention of some, but not all, expressed wild-type retinoschisin. Moreover, when the wild-type protein is expressed with a missense mutant that is normally secreted, co-assembly occurs resulting in the secretion of a heterogeneous mixture of oligomers. Missense mutations of retinoschisin which cause intracellular retention also lead to an unfolded protein response. However, this is not sufficient to decrease cell viability suggesting that the pathology of the disease is not likely to be linked to programmed cell death.