Recurrent germline mutation in MSH2 arises frequently de novo

• Published in: Journal of Medical Genetics
• Main Authors: Gao, X, Desai, DC, Lockman, JC, Chadwick, RB, Percesepe, A, Evans, DGR, Miyaki, M, Yuen, ST, Radice, P, Maher, ER, Wright, FA, De la chapelle, A
• Format: Article in Journal/Newspaper
• Language: English
• Published: B M J Publishing Group. The Journal's web site is located at http://jmg.bmjjournals.com/ 2000
• Subjects: Sequence Analysis; DNA; Colorectal Neoplasms; Hereditary Nonpolyposis - genetics; DNA-Binding Proteins; Germ-Line Mutation; Proto-Oncogene Proteins - genetics; Newfoundland
• Online Access: https://doi.org/10.1136/jmg.37.9.646; http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-2593&volume=37&issue=9&spage=646&epage=652&date=2000&atitle=Recurrent+germline+mutation+in+MSH2+arises+frequently+de+novo; http://hdl.handle.net/10722/46964

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. published_or_final_version