The fragile-X premutation: a maturing perspective

Abstract

Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-X-associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.

Figure 1

Relative in vivo translational efficiencies of FMR1 5′ UTRs (expressed per mRNA molecule), plotted as a function of the number of CGG-trinucleotide repeats. The FMR1 5′ UTRs were placed upstream of a reporter (firefly luciferase) coding sequence, and the resulting CMV-promoter constructs were transfected into either SK-N-MC cells (neuroepithelial origin) (black circles) or 293 cells (fetal kidney epithelium) (gray circles). The graph is normalized to 0 CGG repeats. Figure adapted from Chen et al. (2003).

Figure 2

Schematic representation of our working hypothesis for an RNA toxic gain-of-function model for FXTAS. In this model, (hypothesized) specific protein interactions with the 5′ UTR of the FMR1 mRNA are altered as a consequence of expansion of the CGG repeat; this model is analogous to the RNA gain-of-function model proposed for myotonic dystrophy (see the “An RNA Gain-of-Function Model for FXTAS” section). In the premutation range, the expanded CGG repeat would lead to excess binding of one or more proteins (pink spheres), owing to (i) increased mRNA copy number, (ii) increased number of CGG repeats (increased CGG molarity), and/or (iii) altered secondary/tertiary RNA structure. This excess binding depletes the proteins from the cellular pool, resulting in the loss of their normal functions in other regulatory processes. The sequestration process would also trigger the accumulation or abnormal processing of proteins by the proteasomal degradation pathway, leading to inclusion formation with associated ubiquitinated proteins, proteasomal subunits, and stress-response (HSP) proteins. In the full-mutation range, altered protein-RNA interactions do not occur in the absence of FMR1 mRNA but could occur in the case of a full mutation allele that remains transcriptionally active. Image inset, Inclusion within an isolated neural cell nucleus (frontal cortex) from a patient with FXTAS; the inclusion is stained with fluorescent antiubiquitin antibody, and the nucleus is counterstained with DAPI.