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Site directed mutagenesis of hMLH1 exonic splicing enhancers does not correlate with splicing disruption
  1. P Lastella,
  2. N Resta,
  3. I Miccolis,
  4. A Quagliarella,
  5. G Guanti,
  6. A Stella
  1. Sezione di Genetica Medica, DIMIMP Policlinico Università degli Studi di Bari, Bari, Italy
  1. Correspondence to:
 Dr A Stella
 Sezione di Genetica Medica, DIMIMP Policlinico, P.zza G.Cesare 11 70124 Bari, Italy;

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Hereditary non-polyposis colorectal cancer (MIM 114500) is the most common inherited colorectal cancer syndrome, affecting 1 in 1000 people. Patients with hereditary non-polyposis colorectal cancer show predisposition to an early onset of synchronous and metachronous colorectal cancers in association with a variety of other extra-intestinal malignancies. The disease is caused by germline mutations in one of the five mismatch repair genes (hMLH1, hMSH2, hMSH6, hPMS2, hMLH3).1–6 A common mechanism of mutation in hereditary non-polyposis colorectal cancer is the disruption of hMSH2 and hMLH1 splicing by exon skipping.7,8 In addition, recent reports have shown aberrant splicing to occur even in normal individuals without hereditary cancer predisposition.9–11 However apart from the mutations in the splicing donor and acceptor sites, the effects on splicing of other sequence variations found in a patient are difficult to predict. Exonic sequences have also been shown to affect splicing efficiency; in fact any single base change in these sequences may have potential pathogenic consequences leading to aberrant splicing or exon skipping.12–14 Different mechanisms have been proposed to explain how exonic sequences mediate splicing regulation. Recent reports show that aberrant splicing may occur as a consequence of mutations that disrupt exonic splicing enhancers (ESEs) or create exonic splicing silencers.15–17 Exonic enhancers have been shown to interact specifically with serine or arginine rich (SR) proteins that regulate the splicing process, promoting exon definition by direct recruitment of spliceosome and regulatory proteins or antagonising the action of nearby silencer elements.18,19 Different classes of ESE consensus motifs have been described, but they are not always easily identified. Recently two web based resources ESEfinder ( and RESCUE-ESE ( have been developed to facilitate rapid analysis of exon sequences, to identify putative …

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  • This research was supported, in part, by a grant from Ministero Istruzione Università Ricerca FIRB no RBAU01SZHB (to GG).

  • Conflicts of interest: none declared.