title: Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles.
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Davis, CA, USA. ftassone@ucdavis.edu
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.forename: Chiara
authors.initials: C
authors.lastname: Carosi
authors.forename: Giorgio
authors.initials: G
authors.lastname: La Fata
authors.forename: Gisele
authors.initials: G
authors.lastname: Serpa
authors.forename: Christopher
authors.initials: C
authors.lastname: Raske
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D026723:Polyadenylation; D024363:Transcription Initiation Site; D018911:Trinucleotide Repeats; D020506:Untranslated Regions
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D051860:Fragile X Messenger Ribonucleoprotein 1; D020506:Untranslated Regions; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse