Recurrent germline mutation in MSH2 arises frequently de novo
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 w...
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ftpubmed:oai:pubmedcentral.nih.gov:1734701 2023-05-15T17:22:42+02:00 Recurrent germline mutation in MSH2 arises frequently de novo Desai, D. Lockman, J. Chadwick, R. Gao, X. Percesepe, A. Evans, D Miyaki, M. Yuen, S. T. Radice, P. Maher, E. Wright, F. de la Chapelle, A. 2000-09 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734701 http://www.ncbi.nlm.nih.gov/pubmed/10978353 https://doi.org/10.1136/jmg.37.9.646 en eng BMJ Group http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734701 http://www.ncbi.nlm.nih.gov/pubmed/10978353 http://dx.doi.org/10.1136/jmg.37.9.646 Original Articles Text 2000 ftpubmed https://doi.org/10.1136/jmg.37.9.646 2013-08-31T14:37:27Z 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. Keywords: MSH2; recurrent mutation; splice donor site of exon 5; founder mutation Text Newfoundland PubMed Central (PMC) Journal of Medical Genetics 37 9 646 652 |
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Original Articles Desai, D. Lockman, J. Chadwick, R. Gao, X. Percesepe, A. Evans, D Miyaki, M. Yuen, S. T. Radice, P. Maher, E. Wright, F. de la Chapelle, A. Recurrent germline mutation in MSH2 arises frequently de novo |
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Original Articles |
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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. Keywords: MSH2; recurrent mutation; splice donor site of exon 5; founder mutation |
format |
Text |
author |
Desai, D. Lockman, J. Chadwick, R. Gao, X. Percesepe, A. Evans, D Miyaki, M. Yuen, S. T. Radice, P. Maher, E. Wright, F. de la Chapelle, A. |
author_facet |
Desai, D. Lockman, J. Chadwick, R. Gao, X. Percesepe, A. Evans, D Miyaki, M. Yuen, S. T. Radice, P. Maher, E. Wright, F. de la Chapelle, A. |
author_sort |
Desai, D. |
title |
Recurrent germline mutation in MSH2 arises frequently de novo |
title_short |
Recurrent germline mutation in MSH2 arises frequently de novo |
title_full |
Recurrent germline mutation in MSH2 arises frequently de novo |
title_fullStr |
Recurrent germline mutation in MSH2 arises frequently de novo |
title_full_unstemmed |
Recurrent germline mutation in MSH2 arises frequently de novo |
title_sort |
recurrent germline mutation in msh2 arises frequently de novo |
publisher |
BMJ Group |
publishDate |
2000 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734701 http://www.ncbi.nlm.nih.gov/pubmed/10978353 https://doi.org/10.1136/jmg.37.9.646 |
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Newfoundland |
genre_facet |
Newfoundland |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734701 http://www.ncbi.nlm.nih.gov/pubmed/10978353 http://dx.doi.org/10.1136/jmg.37.9.646 |
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https://doi.org/10.1136/jmg.37.9.646 |
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Journal of Medical Genetics |
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37 |
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9 |
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