CGG-repeat length threshold for FMR1 RNA pathogenesis in a cellular model for FXTAS
Gry Hoem1, Christopher R Raske, Dolores Garcia-Arocena
1Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA 95616, USA.
Human Molecular Genetics
|March 11, 2011
Summary
Fragile X-associated tremor/ataxia syndrome (FXTAS) is linked to FMR1 gene CGG repeats. Toxicity depends on repeat size, with a threshold between 62-95 repeats, and then mRNA concentration.
Area of Science:
- Neurogenetics
- Molecular Biology
- Cellular Toxicology
Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of FMR1 gene premutation alleles.
- The exact mechanisms of mRNA-induced toxicity in FXTAS pathogenesis remain unclear.
- Key questions involve the existence of a CGG-repeat size threshold for toxicity and the role of mRNA concentration.
Purpose of the Study:
- To investigate the independent effects of CGG-repeat number and mRNA concentration on cellular toxicity.
- To determine if a CGG-repeat size threshold exists for FMR1-related cellular dysregulation.
- To elucidate the relationship between mRNA concentration and cell viability at different repeat lengths.
Main Methods:
- Development of a doxycycline-inducible episomal system for controlled gene expression.
- Utilizing neuroblastoma-derived SK cells to study FMR1 gene expression.
- Systematically varying CGG-repeat number and mRNA concentration to assess cellular effects.
Main Results:
- A CGG-repeat size threshold for toxicity was identified, falling between 62 and 95 CGG repeats.
- For repeat sizes of 95 CGG and above, increased mRNA concentration correlated with decreased cell viability.
- Cellular toxicity demonstrates a primary dependence on CGG-repeat size and a secondary dependence on mRNA concentration.
Conclusions:
- Findings support an RNA-toxicity model for FXTAS pathogenesis.
- The results indicate a critical CGG-repeat size threshold for FMR1-mediated toxicity.
- A simple titration model is insufficient to explain FXTAS pathogenesis, suggesting complex RNA-mediated mechanisms.
Related Concept Videos
01:31Translation
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
02:18Alternative RNA Splicing
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...