HNPCC mutation MLHI P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1

Heterozygous germ-line mutations in DNA mismatch repair (MMR) genes predispose individuals to hereditary nonpolyposis colorectal cancer (HNPCC), whereas with homozygous MMR gene mutations children are diagnosed at an early age with de novo neurofibromatosis type I (NFI) and/or hematological malignancies. Here, we describe a mutation, MLHI P648S, which was found in a typical HNPCC family, with one homozygous child displaying mild features of NFI and no hematological cancers. To evaluate the pathogenicity of the mutation, we studied both the expression and the function of the mutated protein. It generally has been assumed that the predisposing mutations prevent the production of a functional protein. The mutated MLH I P648S protein was found to be unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual are linked to shortage of the functional protein. (C) 2004 Wiley-Liss, Inc.