Structure of the Human MSH2 Locus and Analysis of Two Muir-Torre Kindreds for msh2 Mutations

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is a major cancer susceptibility syndrome known to be caused by inheritance of mutations in genes such as hMSH2 and bMLH1, which encode components of a DNA mismatch repair system. The MSH2 genomic locus has been cloned and shown to cover ∼73 kb of genomic DNA and to contain 16 exons. The sequence of all of the intron-exon junctions has been determined and used to develop methods for analyzing each MSH2 exon for mutations. These methods have been used to analyze two large HNPCC kindreds exhibiting features of the Muir-Torre syndrome and demonstrate that cancer susceptibility is due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family.