NAF Ataxia Research Studies Currently Underway

Greg Mayeur, PhD

University of California, Davis
Late Onset Ataxia Due to a CGG Repeat Expansion in the FMR1 Gene

Summary: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a recently discovered ataxia associated with Fragile X Syndrome (FXS). Both FXTAS and FXS result from an expansion of the CGG repeats located in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR 1). FXTAS occurs in older patients classified as premutation for CGG repeat number (55-200 repeats), whereas FXS is found in childhood patients with greater than 200 repeats (full mutation). Despite being caused by the same gene, FXTAS and FXS are caused by entirely distinct molecular mechanisms. While FXS is a protein deficiency disorder caused by gene silencing, FXTAS is caused by elevated expression of expanded repeat mRNA, not lowered levels of the FMR1 protein (FMRP). FXTAS appears to affect primarily older (>50 years) male carriers of premutation alleles, although some female carriers are also affected. The major clinical features of FXTAS include gait ataxia, and progressive intention tremor, with Parkinsonism, and peripheral neuropathy being more variable symptoms. Gait ataxia begins with balance problems, particularly with tandem gait. Walking difficulties progress to the point where successive use of cane, walker, and wheelchair is required. Bases on results of ataxia/tremor screening of adult premutation carriers, and a premutation carrier frequency of 1:800 for males in the general population, an estimated 1:3000 males poses a risk of developing FXTAS over their lifetime. Additionally screens of ataxia populations have identified 2-5% as carriers of the premutation alleles.

Based on the current observations we hypothesize that FXTAS is likely caused by a RNA "toxic I gain-of-function." The four main arguments that support this are: 1) The ataxia is exclusively: confined to carriers of the premutation. 2) The dysregulation of transcription in the premutation: range. 3) A CGG repeat model of FXTAS upstream of a heterogous reporter in Drosophila melanogaster exhibits similar neuropathology. 4) The FMR1 mRNA is found in intranuclear inclusions found in FXT AS patients.

To examine this hypothesis we propose two specific aims: 1) To identify trans-acting factors that interact directly with the FMR 1 CGG repeat, and the potential neurpathologies of this interaction and 2) Identify the transcriptional regulatory factors that lead to elevated FMR1 mRNA levels.