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

• Autores: Nieminen, Taina T.; Pavicic, Walter Hernan; Porkka, Noora; Kankainen, Matti; Järvinen, Heikki J.; Lepistö, Anna; Peltomäki, Päivi
• Año de publicación: 2016
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ALLELE-SPECIFIC EXPRESSION; APC; FAMILIAL ADENOMATOUS POLYPOSIS; PSEUDOEXON; RNA-SEQ
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Nieminen, Taina T.. University of Helsinski; Finlandia
Fil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina. University of Helsinski; Finlandia
Fil: Porkka, Noora. University of Helsinski; Finlandia
Fil: Kankainen, Matti. University of Helsinski; Finlandia
Fil: Järvinen, Heikki J.. University of Helsinski; Finlandia
Fil: Lepistö, Anna. University of Helsinski; Finlandia
Fil: Peltomäki, Päivi. University of Helsinski; Finlandia