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Recurrent Germline Mutation in MSH2 Arises Frequently De Novo

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Recurrent Germline Mutation in MSH2 Arises Frequently De Novo 646 J Med Genet 2000;37:646–652 Division of Surgical J Med Genet: first published as 10.1136/jmg.37.9.646 on 1 September 2000. Downloaded from Oncology, The Ohio Recurrent germline mutation in MSH2 arises State University, 410 W 10th Avenue, N-924 frequently de novo Doan Hall, Columbus, OH 43210, USA D C Desai Darius C Desai, Janet C Lockman, Robert B Chadwick, Xin Gao, Antonio Percesepe, Human Cancer D Gareth R Evans, Michiko Miyaki, Siu Tsan Yuen, Paolo Radice, Eamonn R Maher, Genetics Program, Fred A Wright, Albert de la Chapelle Comprehensive Cancer Center, The Ohio State University, 420 W 12th Avenue, Suite 646, Columbus, Abstract Later, the genomic abnormality was identified OH 43210, USA Introduction—An intronic germline mu- as an exon 5 splice donor site mutation J C Lockman → → R B Chadwick tation in the MSH2 gene, A T at nt942+3, comprising an A T change at the third nucle- X Gao interferes with the exon 5 donor splicing otide of the intron, abbreviated MSH2 IVS5+3 F A Wright mechanism leading to a mRNA lacking A→TorA→T at nt942+3, and the same A de la Chapelle exon 5. This mutation causes typical mutation was identified in two further North hereditary non-polyposis colorectal can- American HNPCC kindreds.3 Subsequently, Department of cer (HNPCC) and has been observed in when four out of 33 kindreds in eastern Internal Medicine, 4 Universita di Modena, numerous probands and families world England were found to have it, a founding Via del Pozzo 71, 41100 wide. Recurrent mutations either arise mutational event in an Anglo-Saxon ancestor Modena, Italy repeatedly de novo or emanate from appeared plausible. It was later shown that as A Percesepe ancestral founding mutational events. The many as 11 out of 41 HNPCC kindreds in A→T mutation had previously been shown Newfoundland had the same mutation, consti- Department of 5 Medical Genetics, St to be enriched in the population of tuting 27% of all known HNPCC families. In Mary’s Hospital, Newfoundland where most families 1999, an in depth study of haplotypes in Hathersage Road, shared a founder mutation. In contrast, in kindreds with the mutation from Newfound- Manchester M13 0JH, England, haplotypes failed to suggest a land, England, and the USA was undertaken to UK founder eVect. If the absence of a founder determine its origin.5 That study concluded DGREvans eVect could be proven world wide, the fre- that in Newfoundland, eight families out of 11 Department of quent de novo occurrence of the mutation studied had identical haplotypes, suggesting a Biochemistry, Tokyo would constitute an unexplored predispo- single founding event. As Newfoundland began Metropolitan Institute sition. to be settled as recently as 1610, this finding of Medical Sciences, Methods—We studied 10 families from was consistent with the observed conserved 3-18-22 England, Italy, Hong Kong, and Japan with haplotype extending over a large region of 10 Honkomagome, a battery of intragenic and flanking poly- Bunkyo-ku, Tokyo 113, cM. In contrast, no clear evidence of haplotype Japan morphic single nucleotide and microsatel- sharing was observed among three US and five M Miyaki lite markers. English families, prompting the suggestion that http://jmg.bmj.com/ Results—Haplotype sharing was not ap- the mutation was unlikely to be the result of a Department of parent, even within the European and world wide ancestral event.5 Pathology, Queen Asian kindreds. Our marker panel was Mary Hospital, The The rationale for undertaking the present University of Hong suYcient to detect a major mutation aris- investigation was that the same mutation began Kong, Pokfulam, Hong ing within the past several thousand to be reported frequently in Europe and Kong generations. Asia.3 6–14 By early 2000, a total of 114 diVerent STYuen Discussion—As a more ancient founder is germline mutations of MSH2 had been listed on September 30, 2021 by guest. Protected copyright. implausible, we conclude that the A→T in the HNPCC database (www.nfdht.nl), and Department of mutation at nt942+3 of MSH2 occurs de Experimental the A→T at nt942+3 was frequently observed. Oncology, Istituto novo with a relatively high frequency. We Indeed, considering both the database and the Nazionale Tumori, Via hypothesise that it arises as a consequence publications cited above, it is by far the most Venezian 1, 20133 of misalignment at replication or recom- commonly reported MSH2 germline mutation. Milano, Italy bination caused by a repeat of 26 adenines, P Radice It currently accounts for 11% of all MSH2 of which the mutated A is the first. It is by germline mutations reported in the HNPCC Section of Medical and far the most common recurrent de novo database. If this were an ancestral mutation Molecular Genetics, germline mutation yet to be detected in a that occurred on several continents including Department of human mismatch repair gene, accounting Asia, its origin would have to be quite ancient. Paediatrics and Child for 11% of all known pathogenic MSH2 It follows that, as a result, the putative Health, University of mutations. conserved and shared haplotype would only Birmingham, The (J Med Genet 2000;37:646–652) Medical School, comprise a very small chromosomal region. Edgbaston, Keywords: MSH2; recurrent mutation; splice donor site Well known examples of conserved ancestral Birmingham B15 2TT, of exon 5; founder mutation haplotypes occurring world wide include the UK region around the â globin gene on chromo- E R Maher somes with the Glu→Val missense mutation in 15 Correspondence to: The large “C” family from Newfoundland that codon 6 leading to sickle cell disease, and the Professor de la Chapelle, allowed hereditary non-polyposis colorectal region of the CFTR gene on chromosomes with [email protected] cancer (HNPCC) to be mapped to the short the ÄF508 mutation responsible for cystic 1 16 Revised version received arm of chromosome 2 was subsequently fibrosis. In both cases the mutation occurs 9 May 2000 shown to have an in frame cDNA deletion of world wide and accounts for a major pro- Accepted for publication 12 MSH2 comprising nucleotides 265-314.2 portion of the respective disease chromosomes. May 2000 www.jmedgenet.com De novo recurrent germline mutation in MSH2 647 Table 1 Characteristics of subjects studied characteristics of the kindreds are shown in J Med Genet: first published as 10.1136/jmg.37.9.646 on 1 September 2000. Downloaded from table 1. All families satisfied the Amsterdam Family Identification Relationship A→T at nt942+3 criteria for HNPCC families. Italy (Milan 1) 1560 Son Yes 1561 Daughter No MARKER IDENTIFICATION AND MAPPING 1581 Son Yes 1587 Mother No Intragenic single nucleotide polymorphisms 1729 Son No (SNPs) were identified using the web site of the 2883 Daughter No International Collaborative Group on Heredi- Italy (Milan 2) 2417 Sister No 2517 Cousin No tary Non-Polyposis Colon Cancer at 2719 Cousin Yes www.nfdht.nl/database/msh2-poly.htm. Three 2412 Brother Yes SNPs were identified as likely to be informative, 3045 Daughter of 2412 Yes Italy (Modena) 1 Father Yes each with allele frequencies at the lesser allele of 2 Child No greater than 20% (c→g at 211+9, t→aat 3 Child No → 4 Child No 1511-9, g a at 1661+12). In addition, six mic- 5 Child No rosatellites within or near MSH2 were identified. England family 1 1 Sib Yes Of these, the three tetranucleotide repeat micro- 2Sib No England family 2 1 Sib Yes satellites are intragenic and mapped relative to 2 Sib Yes the exons, while the remaining three dinucle- 3 Sib Yes otide repeat microsatellites (CA) have not been England family 3 1 Mother Yes 2 Daughter Yes precisely mapped, but have been sequenced on a 3 Daughter Yes BAC containing the MSH2 gene. These three 4 Daughter No CA repeat sequences are within 70 kb of MSH2. 5 Son Yes England family 4 1 Mother Yes Parametric methods for assessing linkage dis- 2 Daughter No equilibrium depend on genomic sequence posi- 3 Daughter Yes tion, but many introns of MSH2 have not yet 4 Daughter No 5 Distant relative Yes been fully sequenced. We used cross_match ver- 6 Distant relative No sion 0.990315 (P Green, unpublished data, Hong Kong 1 Reg 41 Sib Yes Reg 49 Sib No www.phrap.org) to compare MSH2 mRNA and Reg 99 Sib No DNA (accession number AC009600), and to Hong Kong 2 ST99 Daughter Yes obtain relative genomic positions for the mark- ST114 Sib No ST115 Father Yes ers where possible. These markers were typed in Japan 2496 Grandmother No all available family members. Another set of 16 1826 Son Yes SNPs were identified for study, but based on 2497 Grandson No 2498 Grandson Yes published reports are thought to be relatively uninformative. Nonetheless, a fortunate pairing of a disease allele with a low frequency marker Allele sharing at flanking marker loci can be allele may provide powerful evidence for linkage used to estimate the number of generations disequilibrium. These SNPs were thus typed for since founding, provided that the genetic or two subjects in each kindred, in either parent http://jmg.bmj.com/ physical distance between the mutation and child pairs (seven kindreds) or sib pairs (three marker loci is known.17 18 Indeed, using this kindreds) to determine if further typing was strategy, the age of the ÄF508 mutation in warranted. All 16 markers were homozygous for CFTR was tentatively determined as some the major allele in allele typed subjects and thus 54 000 years or over 2000 generations.16 By were not informative for this study.
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