TRANSCRIPTS WITH SPLICINGS OF EXON-15 AND EXON-16 OF THE HMLH1 GENE IN NORMAL LYMPHOCYTES - IMPLICATIONS IN RNA-BASED MUTATION SCREENING OFHEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Germline mutations of the hMLH1 gene are estimated to account for a la rge fraction of kindreds affected by hereditary non-polyposis colorect al cancer (HNPCC). In a significant number of cases, hMLH1 mutations r esult in the expression of truncated proteins. We report here two nove l alternatively spliced forms of hMLH1 mRNA in normal lymphocytes. One of these novel isoforms lacks the coding region of the gene between c odons 557 and 578, corresponding to the entire exon 15. The deletion i ntroduces a frameshift that results in a premature stop signal. The ot her isoform is characterised by an in-frame deletion spanning codons 5 78-632, corresponding to loss of the entire exon 16. Further studies a re necessary to establish the biological significance of these alterna tive splicings. The presence of alternatively spliced hMLH1 transcript s that mimic pathogenic mutations should be taken into account in the mutational screening of the hMLH1 gene by reverse transcription-polyme rase chain reaction methodologies. (C) 1998 Elsevier Science Ltd. All rights reserved.