Research Papers:

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Taina T. Nieminen _, Walter Pavicic, Noora Porkka, Matti Kankainen, Heikki J. Järvinen, Anna Lepistö and Päivi Peltomäki

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Oncotarget. 2016; 7:70685-70698. https://doi.org/10.18632/oncotarget.12206

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Taina T. Nieminen1, Walter Pavicic1,2, Noora Porkka1, Matti Kankainen3, Heikki J. Järvinen4, Anna Lepistö5, Päivi Peltomäki1

1University of Helsinki, Medical and Clinical Genetics, Helsinki, Finland

2Laboratorio de Citogenética y Mutagénesis, Instituto Multidisciplinario de Biología Celular (IMBICE-CONICET-CICPBA), La Plata, Argentina

3University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland

4Second Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland

5Department of Colorectal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland

Correspondence to:

Taina T. Nieminen, email: [email protected]

Keywords: familial adenomatous polyposis, APC, pseudoexon, RNA-seq, allele-specific expression

Received: February 09, 2016    Accepted: September 12, 2016    Published: September 23, 2016


Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.

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