title: A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays.
abstract: Many mismatch repair (MMR) gene disease-causing mutations identified in cancer patients result in aberrant messenger RNA (mRNA) splicing. However, mRNA assay interpretation can be complicated by the existence of naturally occurring alternative mRNA transcripts, most of which have not been formally described or fully characterized. Here, we provide a comprehensive catalogue of all MMR transcripts described to date, and a review of MMR nucleotide variants associated with an apparent upregulation of alternatively spliced transcripts. This work sets reference starting points for designing and interpreting MMR RNA analyses. Our database and literature searches retrieved 30 MLH1, 22 MSH2, 4 MSH6 and 9 PMS2 alternative transcripts, many predicted to introduce premature termination codons. Furthermore, we collected information on 66 MLH1, 24 MSH2 and 6 PMS2 nucleotide variants reported to be associated with altered expression of at least one of these alternative transcripts, and in many instances reported as splicing mutations. This review shows that there are many alternatively spliced MMR transcripts, which have potential to confound interpretation of splicing assays. These findings highlight the need to perform RNA analysis of patients systematically in parallel with control individuals, and call for the implementation of quantitative assessment of transcript levels for informed interpretation of mRNA assays.
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: B A
authors.initials: BA
authors.lastname: Thompson
authors.forename: A
authors.initials: A
authors.lastname: Martins
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D030541:Databases, Genetic; D018095:Germ-Line Mutation; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: Lynch syndrome; MLH1; MSH2; MSH6; PMS2; alternative RNA splicing; mismatch repair; transcript