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Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles
- Tassone, Flora, De Rubeis, Silvia, Carosi, Chiara, La Fata, Giorgio, Serpa, Gisele, Raske, Christopher, Willemsen, Rob, Hagerman, Paul J., Bagni, Claudia
- Nucleic acids research 2011 v.39 no.14 pp. 6172-6185
- 3' untranslated regions, alleles, ataxia (disorder), autism, brain, disease course, females, humans, mice, mutation, neurodegenerative diseases, phenotype, transcription (genetics)
- 5'- and 3'-untranslated regions (UTRs) are important regulators of gene expression and play key roles in disease progression and susceptibility. The 5'-UTR of the fragile X mental retardation 1 (FMR1) gene contains a CGG repeat element that is expanded (>200 CGG repeats; full mutation) and methylated in fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and known cause of autism. Significant phenotypic involvement has also emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), in older adult carriers. Here, we show that FMR1 mRNA in human and mouse brain is expressed as a combination of multiple isoforms that use alternative transcriptional start sites and different polyadenylation sites. Furthermore, we have identified a novel human transcription start site used in brain but not in lymphoblastoid cells, and have detected FMR1 isoforms generated through the use of both canonical and non-canonical polyadenylation signals. Importantly, in both human and mouse, a specific regulation of the UTRs is observed in brain of FMR1 premutation alleles, suggesting that the transcript variants may play a role in premutation-related pathologies.