Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles

Flora Tassone, Silvia De Rubeis, Chiara Carosi, Giorgio La Fata, Gisele Serpa, Christopher Raske, Rob Willemsen, Paul J Hagerman, Claudia Bagni

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6172-6185
Number of pages14
JournalNucleic Acids Research
Volume39
Issue number14
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Genetics

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