Tissue-specific reduction in MLH1 expression induces microsatellite instability in intestine of Mlh1 mice.

Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson's two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis.

Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm.

DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites.