Point mutations in follitropin receptor result in ER retention.

Accumulating evidence suggests that the human follitropin receptor is unusually sensitive to mutation. Previous results (Mol. Cell. Endo. 166 (2000) 101) determined that scanning mutations in a.a. 12-14 and 22-30 neither bound follitropin nor were present on the cell surface, suggesting that these regions are involved in either hormone binding or trafficking. To distinguish between these hypotheses, single alanine substitutions in a.a. 12-14 and 22-30 were generated, all of which appeared to bind 125I-follitropin with an affinity constant similar to wild type (wt) follitropin receptor. However, the level of receptor on the cell surface varied widely, in some cases 100-fold lower than wt. Expression on the cell surface corresponded to expression of the mature 80 kD follitropin receptor. An accumulation of the ER-resident 62 kD band of follitropin receptor was observed in mutants that had low surface expression of receptor, suggesting that misfolded protein was trapped in the ER by a quality control mechanism.