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[Cancer Research 63, 3302-3308, June 15, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

A Yeast Two-Hybrid Assay Provides a Simple Way to Evaluate the Vast Majority of hMLH1 Germ-Line Mutations1

Emiko Kondo, Hideyuki Suzuki, Akira Horii and Shinichi Fukushige2

Department of Molecular Pathology, Tohoku University School of Medicine, Miyagi 980-8575, Japan

Germ-line mutations in the hMLH1 gene are the most frequent cause of hereditary nonpolyposis colorectal cancer and are characterized by missense mutations at high frequency. We found a yeast two-hybrid assay to be an extremely useful and simple tool for evaluating the biological significance of such hMLH1 germ-line missense mutations; 78% (18 of 23) of the missense ones can be recognized as causative for nonpolyposis colorectal cancer. In addition, two of five variants not recognized as causative were thought to be rare polymorphisms. However, we could not detect any differences between wild-type hMLH1 and any of the nine already known polymorphisms causing amino acid alterations. Additional analysis demonstrated that the two-hybrid assay not only detected the dysfunctions at the COOH terminus of the hMLH1 protein necessary for the interaction with associated proteins but also detected a conformational change at the NH2 terminus carrying ATPase activity. Thus, this method provides a simple and reliable system for accurate diagnosis of hMLH1 alterations.




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Copyright © 2003 by the American Association for Cancer Research.