Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome
Article first published online: 20 JAN 2009
Copyright © 2009 Wiley-Liss, Inc.
Genes, Chromosomes and Cancer
Volume 48, Issue 4, pages 340–350, April 2009
How to Cite
Ou, J., Rasmussen, M., Westers, H., Andersen, S. D., Jager, P. O., Kooi, K. A., Niessen, R. C., Eggen, B. J. L., Nielsen, F. C., Kleibeuker, J. H., Sijmons, R. H., Rasmussen, L. J. and Hofstra, R. M. W. (2009), Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome. Genes Chromosom. Cancer, 48: 340–350. doi: 10.1002/gcc.20644
- Issue published online: 3 FEB 2009
- Article first published online: 20 JAN 2009
- Manuscript Revised: 27 NOV 2008
- Manuscript Accepted: 27 NOV 2008
- Manuscript Received: 15 AUG 2008
- The Dutch Cancer Society. Grant Number: RUG2002-2678
- The European Community. Grant Numbers: FP6-2004-LIFESCIHEALTH-5, proposal No 018754
- The Danish Cancer Society, Danish Research Council
So far 18 MLH3 germline mutations/variants have been identified in familial colorectal cancer cases. Sixteen of these variants are amino acid substitutions of which the pathogenic nature is still unclear. These substitutions are known as unclassified variants or UVs. To clarify a possible role for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary colorectal cancer, including Lynch syndrome. © 2009 Wiley-Liss, Inc.