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A Nonsense Mutation in MLH1 Causes Exon Skipping in Three Unrelated HNPCC Families¹

University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 [A. S., K. S., B. L.]; Sez. di Genetica Medica-DIMIMP Policlinico, Universitèa di Bari, 70124 Bari, Italy [A. S., G. G.]; Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands [A. W., R. F.]; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [S. M. L.]; and Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178 [P. W., H. T. L.]

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 are responsible for the majority of hereditary nonpolyposis colorectal cancer (HNPCC) families. A common mutation mechanism is to disrupt MLH1 and MSH2 mRNA splicing. The disruption creates aberrant mRNAs lacking specific coding exons (exon skipping). Here, we report a novel skipping of MLH1 exon 12 caused by an AAG to TAG nonsense mutation at codon 461 in three HNPCC families of North American origins. The nonsense codon was found in a conserved haplotype in the three unrelated families and seems to represent a founder mutation. The skipping created an aberrant MLH1 mRNA transcript lacking exon 12. The effect of the codon 461 nonsense mutation on exon 12 skipping is evident even though it was placed in a minigene construct containing entirely different coding sequences. Notably, the effect of the nonsense mutation on exon skipping is incomplete. Accordingly, a second aberrant MLH1 transcript encompassing the nonsense codon is also produced. Whereas the latter transcript is unstable, presumably because of nonsense-mediated mRNA decay, neither of the aberrant transcripts seems to affect the stability of wild-type MLH1 mRNA. This study demonstrates that the germ-line nonsense mutation at codon 461 of MLH1 disrupts normal MLH1 mRNA processing, and that exon skipping underlies pathogenesis in these HNPCC families.

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