Recurrent germline mutation in MSH2arises frequently de novo
- Darius C Desaia,
- Janet C Lockmanb,
- Robert B Chadwickb,
- Xin Gaob,
- Antonio Percesepec,
- D Gareth R Evansd,
- Michiko Miyakie,
- Siu Tsan Yuenf,
- Paolo Radiceg,
- Eamonn R Maherh,
- Fred A Wrightb,
- Albert de la Chapelleb
- aDivision of Surgical Oncology, The Ohio State University, 410 W 10th Avenue, N-924 Doan Hall, Columbus, OH 43210, USA, bHuman Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, 420 W 12th Avenue, Suite 646, Columbus, OH 43210, USA, cDepartment of Internal Medicine, Universita di Modena, Via del Pozzo 71, 41100 Modena, Italy, dDepartment of Medical Genetics, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK, eDepartment of Biochemistry, Tokyo Metropolitan Institute of Medical Sciences, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113, Japan, fDepartment of Pathology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, gDepartment of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy, hSection of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK
- Professor de la Chapelle, delachapelle-1{at}medctr.osu.edu
- Revised 9 May 2000
- Accepted 12 May 2000
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 pathogenicMSH2 mutations.
