The National Ataxia Foundation (NAF) recently awarded funding for 23 promising ataxia research projects. The project led by Dr. Padmaja Vittal from Rush University Medical Center in Chicago received the “Clinical Research Training Fellowship in Ataxia Award” that helps fund the training of the next generation of clinical researchers, which represents the transition between discovery and treatment of the disease. Dr. Vittal’s project is entitled “The Role of Antisense FMR1 in the Development of Fragile X-associated Tremor/Ataxia Syndrome” and the award includes a two-year period fellowship that will be funded by the NAF in collaboration with the American Brain Foundation.
Fragile X-associated tremor/ataxia syndrome (FXTAS) corresponds to one of three known fragile X disorders that are caused by gene alterations in the fragile X gene. It is an inherited neurodegenerative disease that causes memory impairment, tremor and ataxia (loss of voluntary coordination of muscle movements). This disorder usually develops late in life, mainly affecting males over 50 years of age.
“FXTAS is caused by a 55-200 CGG repeat expansion (premutation) in the fragile X mental retardation 1 (FMR1) gene located on the X chromosome. This gene is essential for normal brain development. Elongated CGG repeats resulting from the repeat expansion renders the protein product of the FMR1 gene toxic to the cell,” explained Dr. Vittal. One out of every 500 men and one out of 250 women are estimated to be carriers of the FMR1 premutation. In the United States, 1.6 in every 2000 men is thought to be at risk for FXTAS development.
Usually, the severity of the disease is related to the number of CGG trinucleotide repeats present in the FMR1 gene, but it does not solely account for the risk of developing this disorder. The goal of this project is to determine whether additional secondary genes or molecular events linked to the premutation expansion could lead to an increased risk for FXTAS development.
Within the CGG trinucleotide repeat element of FMR1, AGG repeats have been found. In a normal FMR1 gene, two to three AGG interruptions can be found, while this number decreases in premutation alleles, suggesting that the loss of AGG interruptions within the CGG repeat element may increase the probability of neurodegenerative symptoms. A second gene, called antisense fragile X mental retardation gene (ASFMR), which can present more than one variant in terms of RNA (the messenger of the genetic information), is also thought to be involved in FXTAS disorder.
Dr. Vittal’s goal is to assess the ASFMR gene variants, the importance of CGG repeat size and AGG interruptions, and to determine a possible link between them and the symptomatology in FXTAS patients. “The hope is that this research would allow us to predict if patients will develop symptoms of the disease or remain symptom free. There is a critical need for enhanced screening tools to help families of patients suffering from this disorder, so timely treatment can be implemented,” concluded Dr. Vittal.