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Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

Authors :
van der Klift HM
Tops CM
Bik EC
Boogaard MW
Borgstein AM
Hansson KB
Ausems MG
Gomez Garcia E
Green A
Hes FJ
Izatt L
van Hest LP
Alonso AM
Vriends AH
Wagner A
van Zelst-Stams WA
Vasen HF
Morreau H
Devilee P
Wijnen JT
Source :
Human mutation [Hum Mutat] 2010 May; Vol. 31 (5), pp. 578-87.
Publication Year :
2010

Abstract

Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, co-amplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene-specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3' end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/120) of individuals. We demonstrate that mutation scanning with PMS2-specific PCR primers and MLPA probes, designed on PSVs, in the 3' duplicated region is unreliable, and present an RNA-based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV-based mutation detection methods.<br /> ((c) 2010 Wiley-Liss, Inc.)

Details

Language :
English
ISSN :
1098-1004
Volume :
31
Issue :
5
Database :
MEDLINE
Journal :
Human mutation
Publication Type :
Academic Journal
Accession number :
20186688
Full Text :
https://doi.org/10.1002/humu.21229