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.

Recurrent germline mutation in MSH2 arises frequently de novo / Desai, D. C.; Maher, E. R.; Wright, F. A.; de la Chapelle, A.; Lockman, J. C.; Chadwick, R. B.; Gao, X.; Percesepe, A.; Evans, D. G. R.; Miyaki, M.; Yuen, S. T.; Radice, P.. - In: JOURNAL OF MEDICAL GENETICS. - ISSN 0022-2593. - 37:9(2000), pp. 646-652.

Recurrent germline mutation in MSH2 arises frequently de novo

Percesepe, A.;
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 pathogenic MSH2 mutations.
Recurrent germline mutation in MSH2 arises frequently de novo / Desai, D. C.; Maher, E. R.; Wright, F. A.; de la Chapelle, A.; Lockman, J. C.; Chadwick, R. B.; Gao, X.; Percesepe, A.; Evans, D. G. R.; Miyaki, M.; Yuen, S. T.; Radice, P.. - In: JOURNAL OF MEDICAL GENETICS. - ISSN 0022-2593. - 37:9(2000), pp. 646-652.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2845467
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