Different molecular mechanisms underlie genomic deletions in the MLH1 gene

Alessandra Viel, Fiorella Petronzelli, Lara Della Puppa, Emanuela Lucci-Cordisco, Mara Fornasarig, Salvatore Pucciarelli, Valentina Rovella, Michele Quaia, Maurizio Ponz De Leon, Mauro Boiocchi, Maurizio Genuardi

Research output: Contribution to journalArticlepeer-review


In this study we examined a series of 52 patients belonging to hereditary nonpolyposis colorectal cancer (HNPCC) or HNPCC-related families, all who had previously tested negative for mismatch repair (MMR) gene point mutations. Southern blot mutational screening of MLH1 and MSH2 genes was carried out with the aim of detecting large genomic rearrangements and of identifying the molecular mechanisms underlying the inactivation of the MMR genes. Three patients had abnormal restriction patterns and were found to carry distinct MLH1 internal deletions. Long-range PCRs identified the loss of DNA tracts spanning exon 6 (about 2.4 kb in proband A-AV20 and 0.8 kb in proband A-PD5) and exon 3 (about 2.5 kb in proband R-RM2). In A-AV20 the breakpoints occurred into identical 33-bp regions in introns 5 and 6 and a mechanism of classical Alu-mediated homologous recombination was evident. Also, in patient A-PD5 the breakpoints were located in these introns, but without direct involvement of repetitive sequences. In patient R-RM2 the breakpoints were located within repetitive L1 elements with poor homology in intron 2 and 3 and the rearranged allele was characterized by a complex insertion deletion (delCCinsACATAGTA), giving rise to a palindromic CTTAACATAGTATGTTAAG sequence in proximity of the fusion site. This study confirms that genomic rearrangements are an important component of the spectrum of MMR mutations. Although Alu repeats are likely to be implicated in the majority of cases, different molecular mechanisms may also be responsible for the observed MLH1 intragenic deletions. In particular, HNPCC resulting from L1-mediated recombination has been identified as a novel mechanism for MMR inactivating mutation.

Original languageEnglish
Pages (from-to)368-374
Number of pages7
JournalHuman Mutation
Issue number5
Publication statusPublished - 2002


  • Alu
  • Colorectal cancer
  • L1
  • Mismatch repair
  • MLH1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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