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.

Psychosis and catatonia in fragile X: Case report and literature review

“…In those with FXTAS there is inclusion formation in both neurons and astroglial cells in the brain and in the peripheral nervous system and these inclusions have the excess FMR1 mRNA, fragile X mental retardation protein (FMRP) and many other proteins and neurofilaments (11)(12)(13). Decreased levels of FMRP are observed in some premutation carriers due to reduced translational efficiency of FMR1 mRNA containing the expanded CGG repeat (14)(15)(16). Lowered FMRP in the premutation range will often lead to neurodevelopmental problems including intellectual disability (ID), ASD and ADHD (1), although additional environmental or medical problems such as seizures, trauma, toxins or additional genetic mutations may also cause further developmental problems in these carriers (17)(18)(19).…”

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

“…First, a consistent molecular feature in both FXTAS patients and mouse models is the elevation of aberrant CGG expanded FMR1 mRNA levels (Allen et al 2004;Kenneson et al 2001;Tassone et al 2000), due to increased transcription (Tassone et al 2007). Nevertheless, carriers of premutation alleles show decreased levels of FMRP (Brouwer et al 2008;Entezam et al 2007) caused by the reduced translational efficiency of the FMR1 mRNA carrying the CGG expansion (Primerano et al 2002), as well as by a differential use of the FMR1 mRNA 3 0 UTR (Tassone et al 2011). It has been proposed that the CGG expansion in the 5 0 UTR would form a secondary structure inhibiting the ribosome scanning and thus leading to a scarce translational efficiency (Feng et al 1995).…”

An Evolutionary Biology Approach to Understanding Neurological Disorders

“…Mutation of FMR1 is best characterised as the cause of fragile X syndrome mental retardation, which is inherited in an X-linked dominant pattern, and is due to a lack of FMR1 mRNA and protein expression. However, mutations leading to high levels of FMR1 mRNA are linked to tremor/ataxia syndrome via mRNA 'toxicity', while the gene is also linked to premature ovarian insufficiency via a third uncharacterized molecular pathway, possibly affecting the production of FMR1 mRNA isoforms (Oostra & Willemsen, 2009;Tassone et al, 2011).…”