Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients

Venesio, Tiziana; Balsamo, Antonella; Sfiligoi, Christian; Fuso, Luca; Molatore, Sara; Ranzani, Guglielmina Nadia; Risio, Mauro

doi:10.1007/s00109-006-0127-4

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…The mutation described here results in a predominant exon13-exon15 splice form that is predicted to lead to a translational frameshift and protein truncation product at what would normally be codon 673 in the APC transcript. It is clear from our work and that of others’, that alternative splicing of exon 14 is a normal low-level event in colonic epithelium as well as in peripheral blood lymphocytes (Aretz, et al, 2004; Bala, et al, 1997; Venesio, et al, 2007). Some reports have suggested a possible functional role for such alternate splice forms in normal regulation of gene expression, perhaps by modulating total transcript or full length protein levels (Sulekova, et al, 1995).…”

Section: Discussionsupporting

confidence: 72%

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

et al. 2009

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Familial Adenomatous Polyposis (FAP [OMIM 175100]) is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of the APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with sequences from chromosome 6q22.1. This mutation tracks to members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon13-exon15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as-yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.

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Section: Discussionsupporting

confidence: 72%

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

et al. 2009

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“…For the same reasons, a large subset of single nucleotide polymorphisms (SNPs) found within the human population may modulate alternative splicing. For example, a SNP in an SRp40 binding site in the APC gene correlates with exon omission and attenuated familial adenomatous polyposis [90]. These differences may predispose some individuals to develop certain types of cancers, while other polymorphisms may increase their resistance.…”

Section: Mutations At Splice Sites and In Auxiliary Elementsmentioning

confidence: 97%

Cancer-Associated Perturbations in Alternative Pre-messenger RNA Splicing

Shkreta

Bell

Revil

et al. 2013

Cancer Treatment and Research

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For most of our 25,000 genes, the removal of introns by pre-messenger RNA (pre-mRNA) splicing represents an essential step toward the production of functional messenger RNAs (mRNAs). Alternative splicing of a single pre-mRNA results in the production of different mRNAs. Although complex organisms use alternative splicing to expand protein function and phenotypic diversity, patterns of alternative splicing are often altered in cancer cells. Alternative splicing contributes to tumorigenesis by producing splice isoforms that can stimulate cell proliferation and cell migration or induce resistance to apoptosis and anticancer agents. Cancer-specific changes in splicing profiles can occur through mutations that are affecting splice sites and splicing control elements, and also by alterations in the expression of proteins that control splicing decisions. Recent progress in global approaches that interrogate splicing diversity should help to obtain specific splicing signatures for cancer types. The development of innovative approaches for annotating and reprogramming splicing events will more fully establish the essential contribution of alternative splicing to the biology of cancer and will hopefully provide novel targets and anticancer strategies. Metazoan genes are usually made up of several exons interrupted by introns. The introns are removed from the pre-mRNA by RNA splicing. In conjunction with other maturation steps, such as capping and polyadenylation, the spliced mRNA is then transported to the cytoplasm to be translated into a functional protein. The basic mechanism of splicing requires accurate recognition of each extremity of each intron by the spliceosome. Introns are identified by the binding of U1 snRNP to the 5' splice site and the U2AF65/U2AF35 complex to the 3' splice site. Following these interactions, other proteins and snRNPs are recruited to generate the complete spliceosomal complex needed to excise the intron. While many introns are constitutively removed by the spliceosome, other splice junctions are not used systematically, generating the phenomenon of alternative splicing. Alternative splicing is therefore the process by which a single species of pre-mRNA can be matured to produce different mRNA molecules (Fig. 1). Depending on the number and types of alternative splicing events, a pre-mRNA can generate from two to several thousands different mRNAs leading to the production of a corresponding number of proteins. It is now believed that the expression of at least 70 % of human genes is subjected to alternative splicing, implying an enormous contribution to proteomic diversity, and by extension, to the development and the evolution of complex animals. Defects in splicing have been associated with human diseases (Caceres and Kornblihtt, Trends Genet 18(4):186-93, 2002, Cartegni et al., Nat Rev Genet 3(4):285-98, 2002, Pagani and Baralle, Nat Rev Genet 5(5):389-96, 2004), including cancer (Brinkman, Clin Biochem 37(7):584-94, 2004, Venables, Bioessays 28(4):378-86, 2006, Srebrow and Kornblihtt, J ...

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“…Small decreases in APC mRNA have been detected in APC (−)14,15 and APC (−)/ MUTYH (−) families16-18. In contrast, high germline levels of an APC mRNA isoform resulting from an exon 10-15 connection have been observed in a case of APC (−)/ MUTYH (−) AFAP19. Germline imbalances in allele-specific expression (ASE) of the APC gene have been detected in FAP and AFAP families14, 15, 18, 20, but their potential contribution to diagnostic yield is unknown.…”

Section: Background and Aimsmentioning

confidence: 98%

Allele-Specific Expression of APC in Adenomatous Polyposis Families

et al. 2010

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Backgound & Aims-Germline mutations of the APC gene are the pathogenic cause of most cases of familial adenomatous polyposis (FAP) and a lesser proportion of attenuated FAP (AFAP). Systematic analysis of APC at the RNA level may provide insight into the pathogenicity of identified mutations and uncover the molecular basis of FAP/AFAP in families without identifiable mutations. Here, we analyzed the prevalence of imbalances in the allelic expression of APC in polyposis families with germline mutations in the gene and without detectable mutations in APC or and MUTYH.Methods-Allele-specific expression (ASE) was determined by single nucleotide primer extension using an exon 11 polymorphism as an allele-specific marker. In total, 52 APC-mutationpositive (36 families) and 24 APC/MUTYH-mutation-negative (23 families) informative patients were analyzed. Seventy-six controls were also included.Results-Of the APC-mutation-positive families, most of those in which the mutation was located before the last exon of the gene (12 of 14) showed ASE imbalance, which is consistent with a mechanism of nonsense-mediated decay (NMD). Of the APC/MUTYH mutation-negative families, two (9%) showed ASE imbalance as a hallmark of the putative pathogenic cause of the disease. Normal allele expression was restored after treatment of short-term cultured lymphocytes with puromycin, supporting the NMD hypothesis.Conclusions-ASE analysis may be an indicator of pathogenicity for some cases of FAP and AFAP in which APC mutations are not found. ASE might also be useful for prioritizing the order in which different areas of APC should be tested. Our results underline the importance of RNAlevel studies in molecular diagnosis of FAP.

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Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients

Cited by 15 publications

References 26 publications

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

Cancer-Associated Perturbations in Alternative Pre-messenger RNA Splicing

Allele-Specific Expression of APC in Adenomatous Polyposis Families

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