Distinct patterns of germ-line deletions inMLH1 andMSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC)

Abstract

A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P =0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alumediated unequal recombination is the main type of deletion in MSH2 (n = 34), but not in MLH1 (n = 21) (P <0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.

Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer

“…18 In contrast, MLH1 genomic deletions have been found to involve not only Alu repeats, but also nonhomologous sequences. 2,3,9,20,21 As expected, exonic MSH2 and MLH1 duplications, the reciprocal genomic alterations of deletions resulting from unequal crossingover, have also been detected in HNPCC families, but at a much lower frequency. We reported, using QMPSF, the first case of a MSH2 duplication involving exons 9 -10 that was confirmed by long-range PCR 5 and we subsequently detected another MSH2 duplication involving exons 7 -8.…”

“…2 -24 We previously estimated that genomic deletions of MSH2 and MLH1 respectively, account for approximately 10 and 4% of HNPCC families fulfilling Amsterdam criteria. 6,13 All the MSH2 genomic deletions detected so far have been shown to result from unequal Alu-mediated recombinations 6,8,11,12,18,20 and we found that the density of Alu S repeats within the MSH2 5 0 region was remarkably high, compared with other human genes. 18 In contrast, MLH1 genomic deletions have been found to involve not only Alu repeats, but also nonhomologous sequences.…”

Repetitive sequence environment distinguishes housekeeping genes

“…Indeed, there are numerous reports of disease-causing deletions resulting from recombination between Alu elements (Batzer and Deininger, 2002;Nishimura et al, 2005;Casarin et al, 2006;Has et al, 2006;Kozak et al, 2006;Li et al, 2006;Matejas et al, 2006;Nissen et al, 2006;Sen et al, 2006;Shabbeer et al, 2006;Uddin et al, 2006;Xie et al, 2006;Zhang et al, 2006). If a large proportion of Alu elements indeed fosters euchromatic domains as suggested by the aforementioned study (Willoughby et al, 2000), then flanking sequences may also be destabilized.…”

A novel complex mutation in MSH2 contributes to both Muir-Torre and Lynch Syndrome

“…Previous reports document two large germline MLH1 deletions in which the break points mapped to an L1 element and nonrepetitive DNA sequence, respectively. 12 Viel et al, reported a 2454-bp deletion in MLH1, likely because of the recombination between two L1 elements in intron 2 and intron 3. 13 Interestingly, this allele with the MLH1 deletion was also characterized by a complex mutation delCCinsACATAGTA, which gave rise to a palindromic sequence in the proximity of the fusion site.…”