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Review
. 2009 Sep 5;150B(6):782-98.
doi: 10.1002/ajmg.b.30910.

The FMR1 gene and fragile X-associated tremor/ataxia syndrome

J R Brouwer  1 , R Willemsen, B A Oostra
Affiliations
Review

The FMR1 gene and fragile X-associated tremor/ataxia syndrome

J R Brouwer et al. Am J Med Genet B Neuropsychiatr Genet. .

Abstract

The CGG-repeat present in the 5'UTR of the FMR1 gene is unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In fragile X patients, a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The gene product FMRP is involved in regulation of transport and translation of certain mRNA in the dendrite, thereby affecting synaptic plasticity. This is central to learning and memory processes. The absence of FMRP seen in FM is the cause of the mental retardation seen in fragile X patients. The premutation (PM) is defined as 55-200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Recently it was discovered that elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome. Although arising from the mutations in the same gene, distinct mechanisms lead to fragile X syndrome (absence of FMRP) and FXTAS (toxic RNA gain of function). The pathogenic mechanisms thought to underlie these disorders are discussed, with a specific emphasis on FXTAS. This review gives insight on the implications of all possible repeat length categories seen in fragile X families.

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Figures

FIG. 1
FIG. 1
(CGG)n length and FMR1 expression and clinical outcome. This figure shows the consequences of the different repeat length categories on transcription, translation and clinical phenotype.
FIG. 2
FIG. 2
The prezygotic model of expansion of the fragile X mutation. This model assumes that an expansion of a maternal PM to an FM takes place during meiosis. The fertilized oocyte carries an FM allele. After separation from the embryo proper, the primordial germ cells (PGCs) have an FM. Some alleles will contract to PMs. To explain why FMs are only transmitted through females, some selection must exist agains FMs in the male germ line during spermatogenesis. In the mature testes, PM alleles predominate. In somatic cells and the female germ line, this selection did not take place. Cells with a PM are shown in green and cells with an FM are depicted in orange.
FIG. 3
FIG. 3
Ubiquitin-positive intranuclear inclusions, the neuropathological hallmark of FXTAS in A: human neurons, B: human astrocytes, C: murine neurons. No inclusions have been seen in murine astrocytes.
FIG. 4
FIG. 4
A schematic representation of the RNA gain-of-function mechanism proposed for the pathogenesis of FXTAS. The FMR1 gene is transcribed in the nucleus and transported to the ribosomes. The expanded (CGG0)n present in the 5′UTR of the FMR1 gene hampers translation, leading to lower FMRP levels. Through an as yet unknown mechanism, transcription is upregulated, leading to increased FMR1 mRNA levels. In an attempt to get rid of the excess of FMR1 mRNA, the cell might attract chaperones or elements of the ubiquitin/proteasome system. Also (CGG)n-binding proteins might be recruited. These processes could lead to formation of intranuclear inclusions. Sequestration of proteins into the inclusions might prevent them from exerting their normal function, thereby disturbing cellular function, which in the end might cause neurodegeneration. Also, it cannot be excluded that neuroprotection takes place, such that cells that are capable of capturing the toxic transcripts in the inclusions are the cells that survive.
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