Recurrent germline mutation in MSH2arises frequently de novo. Issue 9 (1st September 2000)

• Record Type: Journal Article
• Authors: Desai, Darius C; Lockman, Janet C; Chadwick, Robert B; Gao, Xin; Percesepe, Antonio; Evans, D Gareth R; Miyaki, Michiko; Yuen, Siu Tsan; Radice, Paolo; Maher, Eamonn R; Wright, Fred A; de la Chapelle, Albert
• Is Part Of: Journal of medical genetics. Volume 37:Issue 9(2000)
• Page Start: 646
• Page End: 652
• Publication Date: 2000-09-01
• Subjects: MSH2 -- recurrent mutation -- splice donor site of exon 5 -- founder mutation; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.37.9.646
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : INTRODUCTION: An intronic germline mutation in the MSH2 gene, A→T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A→T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A→T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.