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Article: Recurrent germline mutation in MSH2 arises frequently de novo

TitleRecurrent germline mutation in MSH2 arises frequently de novo
Authors
Issue Date2000
PublisherB M J Publishing Group. The Journal's web site is located at http://jmg.bmjjournals.com/
Citation
Journal of Medical Genetics, 2000, v. 37 n. 9, p. 646-652 How to Cite?
AbstractINTRODUCTION: 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.
Persistent Identifierhttp://hdl.handle.net/10722/46964
ISSN
2015 Impact Factor: 5.65
2015 SCImago Journal Rankings: 3.820
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDesai, DCen_HK
dc.contributor.authorLockman, JCen_HK
dc.contributor.authorChadwick, RBen_HK
dc.contributor.authorGao, Xen_HK
dc.contributor.authorPercesepe, Aen_HK
dc.contributor.authorEvans, DGRen_HK
dc.contributor.authorMiyaki, Men_HK
dc.contributor.authorYuen, STen_HK
dc.contributor.authorRadice, Pen_HK
dc.contributor.authorMaher, ERen_HK
dc.contributor.authorWright, FAen_HK
dc.contributor.authorDe la chapelle, Aen_HK
dc.date.accessioned2007-10-30T07:02:33Z-
dc.date.available2007-10-30T07:02:33Z-
dc.date.issued2000en_HK
dc.identifier.citationJournal of Medical Genetics, 2000, v. 37 n. 9, p. 646-652en_HK
dc.identifier.issn0022-2593en_HK
dc.identifier.urihttp://hdl.handle.net/10722/46964-
dc.description.abstractINTRODUCTION: 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.en_HK
dc.format.extent263765 bytes-
dc.format.extent1774 bytes-
dc.format.mimetypeapplication/pdf-
dc.format.mimetypetext/plain-
dc.languageengen_HK
dc.publisherB M J Publishing Group. The Journal's web site is located at http://jmg.bmjjournals.com/en_HK
dc.rightsJournal of Medical Genetics. Copyright © B M J Publishing Group.en_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - geneticsen_HK
dc.subject.meshDNA-Binding Proteinsen_HK
dc.subject.meshGerm-Line Mutationen_HK
dc.subject.meshProto-Oncogene Proteins - geneticsen_HK
dc.subject.meshSequence Analysis, DNAen_HK
dc.titleRecurrent germline mutation in MSH2 arises frequently de novoen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://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+novoen_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1136/jmg.37.9.646en_HK
dc.identifier.pmid10978353en_HK
dc.identifier.pmcidPMC1734701-
dc.identifier.isiWOS:000089298800002-

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