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Deciphering Fragile X-Associated Diseases

 

Deciphering Fragile X-Associated Diseases Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder mainly affecting men 50 to 80 years old. The syndrome is associated with a host of problems including tremors, imbalance, numbness in the feet, and memory loss including dementia.

FXTAS is caused by a genetic alteration in the Fragile X mental retardation (FMR1) gene whereby a portion of the gene containing the DNA trinucleotide “CGG” gets repeated in a region of the gene known to control gene activity -- the 5’ untranslated region. While most people have between 6 and 45 CGG repeats in their FMR1 gene, people with FXTAS have between 55 to 200 CGG repeats in their FMR1 gene. Having extra CGG repeats is thought to produce five to ten times more defective FMR1 RNA than usual. The defective RNA cannot be used make the FMR1 protein needed for neurons to develop normally. Instead, the defective protein accumulates in the neurons where it can be toxic to them.

Interestingly, people who have greater than 200 CGG repeats in their FMR1 gene have a related condition called Fragile X syndrome that occurs at birth as opposed to later in life. Fragile X syndrome is associated with mental retardation, attention deficit hyperactivity disorder (ADHD) and severe anxiety, and genetically predisposes an individual to the development of autism. In Fragile X syndrome, the FMR1 gene is “silenced” because the extra CGG repeats change the gene’s structure so much that the cell cannot produce RNA from the gene. This, in turn, disrupts the regulation of other genes involved in neurodevelopment. The number of CGG repeats in the FMR1 gene actually tends to increase with each generation such that there are grandfathers with FXTAS that have grandsons with Fragile X syndrome.

Dr. Paul Hagerman and colleagues at the Neurotherapeutics Research Institute at the University of California-Davis, one of nine Interdisciplinary Research Consortia funded by the Common Fund, are exploring whether FXTAS is a late onset neurodegenerative stage of an early onset neurodevelopmental disorder. That is, is it possible that neurons in people with FXTAS are already damaged by birth as they are in people with Fragile X, since both related disorders involve increased numbers of CGG nucleotide repeats in the same FMR1 gene?

To test their hypothesis, they studied neurons in mouse models of FXTAS that mimic the human disease. In one-day old mice, they found that neurons from the hippocampal region of the brain that functions in memory already looked and functioned abnormally, and by 12 to 24 weeks of age, the mice showed progressive defects in spatial processing. The findings suggest that FXTAS is an end stage disorder that results from a cellular impairment that is present at birth and persists throughout life, highlighting the opportunity to develop early biological, chemical and behavioral interventions.

REFERENCES

Chen Y, Tassone F, Berman RF, Hagerman PJ, Hagerman RJ, Willemsen R and Pessah1 IN. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 2010 19(1):196-208. PMID: 19846466.

Hunsaker MR, Wenzel HJ, Willemsen R, Berman RF. Progressive spatial processing deficits in a mouse model of the fragile X permutation. Behav Neurosci. 2009 Vol 123(6) 1315-1324. PMID: 20001115.

Adams PE, Adams JS, Nguyen DV, Hessl D, Brunberg JA, Tassone F, Zhang W, Koldewyn K, Rivera SM, Grigsby J, Zhang L, DeCarli C, Hagerman PJ, R.J. Hagerman RJ. Psychological Symptoms Correlate With Reduced Hippocampal Volume in Fragile X Premutation Carriers. 2009. Am J Med Genet Part B. PMID: 19908235.
 

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