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a Division of Surgical
Oncology, The Ohio State University, 410 W 10th Avenue, N-924 Doan
Hall, Columbus, OH 43210, USA, b Human Cancer Genetics Program, Comprehensive
Cancer Center, The Ohio State University, 420 W 12th Avenue, Suite 646, Columbus, OH 43210, USA, c Department of Internal Medicine, Universita di
Modena, Via del Pozzo 71, 41100 Modena, Italy, d Department
of Medical Genetics, St Mary's Hospital, Hathersage Road, Manchester
M13 0JH, UK, e Department
of Biochemistry, Tokyo Metropolitan Institute of Medical Sciences,
3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113, Japan, f Department of Pathology, Queen Mary Hospital,
The University of Hong Kong, Pokfulam, Hong Kong, g Department of Experimental Oncology, Istituto
Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy, h Section of Medical and Molecular Genetics,
Department of Paediatrics and Child Health, University of Birmingham,
The Medical School, Edgbaston, Birmingham B15 2TT, UK
Correspondence to: Professor de la Chapelle, delachapelle-1{at}medctr.osu.edu
Revised version received 9 May 2000;
Accepted for publication 12 May 2000
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 AT
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.
METHODSWe studied 10 families from
England, Italy, Hong Kong, and Japan with a battery of intragenic and
flanking polymorphic single nucleotide and microsatellite markers.
RESULTSHaplotype 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.
DISCUSSIONAs a more ancient
founder is implausible, we conclude that the AT 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.
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