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Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer

Hereditary nonpolyposis colon cancer (HNPCC) is associated with malfunction of postreplicative mismatch repair (MMR). While a majority of HNPCC‐associated mutations in the MMR genes MLH1, MSH2, or MSH6 genes cause truncations—and thus loss of function—of the respective polypeptides, little is currently known about the biochemical defects associated with nontruncating mutations. We studied the interactions of six MLH1 variants, carrying either missense mutations or in‐frame deletions, with normal PMS2 and tested the functionality of these heterodimers of MLH1 and PMS2 (MutLα) in an in vitro MMR assay. Three MLH1 carboxy‐terminal mutations, consisting of internal deletions of exon 16 (amino acids 578–632) or exon 17 (amino acids 633–663), or a missense R659P mutation in exon 17, affected the formation of a functional MutLα. Interestingly, mutations C77R and I107R in the amino‐terminal part of MLH1 did not affect its heterodimerization with PMS2. The complexes MLH1(C77R)/PMS2 and MLH1(I107R)/PMS2, however, failed to complement a MMR‐deficient extract lacking a functional MutLα. As all these five mutations were identified in typical HNPCC families and produce nonfunctional proteins, they can be considered disease‐causing. In contrast, the third amino‐terminal mutation S93G did not affect the heterodimerization, and the MLH1(S93G)/PMS2 variant was functional in the in vitro MMR assay, given thus the nature of the HNPCC family in question. Although the missense mutation segregates with the disease, the mean age of onset in the family is unusually high (∼65 years). © 2002 Wiley‐Liss, Inc.