due to biallelic PMS2 germline mutations have been reported. Inheritance of Turcot syndrome can be dominant or recessive. Recessive inheritance of Turcot syndrome is caused by compound heterozygous mutations in PMS2. 31 out of 57 families reported with CMMR-D have germline PMS2 mutations. 19 out of 60 PMS2 homozygous or compound heterozygous mutation carriers had gastrointestinal cancer or adenomas as the first manifestation of CMMR-D. Presence of pseudogenes can cause confusion when identifying mutations in PMS2, leading to false positive conclusions of the presence of mutated PMS2. Deficiency and overexpression Overexpression of PMS2 results in hypermutability and DNA damage tolerance. Deficiency of PMS2 also contributes to genetic instability by allowing for mutations to propagate due to reduced MMR function. It has been shown that PMS2-/- mice developed lymphomas and sarcomas. It was also shown that male mice that are PMS2-/- are sterile, indicating that PMS2 may have a role in spermatogenesis. Role in normal colon PMS2 is usually expressed at a high level in cell nuclei of enterocytes (absorptive cells) within the colonic crypts lining the inner surface of the colon (see image, panel A). DNA repair, involving high expression of PMS2, ERCC1 and ERCC4 (XPF) proteins, appears to be very active in colon crypts in normal, non-neoplastic colonic epithelium. In the case of PMS2, the expression level in normal colonic epithelium is high in 77% to 100% of crypts. Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later. There are 5 to 6 stem cells at the bases of the crypts. If the stem cells at the base of the crypt express PMS2, generally all several thousand cells of the crypt will also express PMS2. This is indicated by the brown color seen by immunostaining of PMS2 in most of the enterocytes in the crypt in panel A of the image in this section. Similar expression of ERCC4 (XPF) and ERCC1 occurs in the thousands of enterocytes in each colonic crypt of the normal colonic epithelium. The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color. Nuclei of cells in the lamina propria (cells which are below and surround the epithelial crypts) largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). Colon cancer About 88% of cells of