English: Diagram depicting the effect of various disease-causing missense mutations on retinoschisin synthesis, protein folding/ER retention, and subunit oligomerization. (a) Wild-type retinoschisin synthesized off of ribosomes associated with the ER membrane is threaded through the translocon and the signal sequence is cleaved by a signal peptidase in the ER lumen to produce the mature folded retinoschisin (RS1) polypeptide. RS1 assembles into a disulphide-linked octameric complex which is exported from cells via the secretory pathway (not shown). (b) Mutations in the signal sequence (L12H and L13P) prevent the insertion of the nascent polypeptide chain into the translocon of the ER resulting in a misfolded polypeptide localized to the cytoplasm where it is rapid degraded by the proteosome. Mutations in the discoidin (DS) domain enable the nascent polypeptide chain to be transported into the ER lumen, but the protein fails to fold into a native conformation and as a result is retained in the ER. Cysteine mutations (C59S and C223R) in the regions flanking the DS domain result in relatively normal protein synthesis, folding, and disulphide-linked dimerization, but fail to further oligomerize into an octameric complex. As a result the retinoschisin dimers are secreted from cells, but are non-functional due to their failure to form disulphide-linked octamers.