The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.
Deschênes, S. M., Tomer, G., Nguyen, M., Erdeniz, N., Juba, N. C., Sepúlveda, N., Pisani, J. E., & Liskay, R. M. (2007). The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair. Cancer Letters, 249(2), 148-156. Doi: 10.1016/j.canlet.2006.08.008