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.

Viel, A., Petronzelli, F., Della Puppa, L., Lucci-Cordisco, E., Fornasarig, M., Pucciarelli, S., et al. (2002). Different molecular mechanisms underlie genomic deletions in the MLH1 Gene. HUMAN MUTATION, 20(5), 368-374 [10.1002/humu.10138].

Different molecular mechanisms underlie genomic deletions in the MLH1 Gene

Rovella, Valentina;
2002

Abstract

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/09
Settore MED/03
Settore MED/18
English
MLH1
mismatch repair
Alu
L1
HNPCC
colorectal cancer
Adaptor Proteins, Signal Transducing
Adult
Alleles
Base Sequence
Carrier Proteins
Colorectal Neoplasms, Hereditary Nonpolyposis
Family Health
Genome, Human
Humans
Molecular Sequence Data
MutL Protein Homolog 1
Neoplasm Proteins
Nuclear Proteins
Sequence Alignment
Sequence Homology, Nucleic Acid
Sequence Deletion
Viel, A., Petronzelli, F., Della Puppa, L., Lucci-Cordisco, E., Fornasarig, M., Pucciarelli, S., et al. (2002). Different molecular mechanisms underlie genomic deletions in the MLH1 Gene. HUMAN MUTATION, 20(5), 368-374 [10.1002/humu.10138].
Viel, A; Petronzelli, F; Della Puppa, L; Lucci-Cordisco, E; Fornasarig, M; Pucciarelli, S; Rovella, V; Quaia, M; Ponz de Leon, M; Boiocchi, M; Genuardi, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/308724
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