Gene found for late-life disorder that causes tremors, affects balance

By Ruth SoRelle, M.P.H.

Once, doctors thought that people who had a "premutation" defect in the gene associated with the syndrome called fragile X were safe.

Then, they began to recognize that this group developed a neurodegenerative disease late in life. This disorder, known as fragile X-associated tremor/ataxia syndrome, is characterized first by tremors that grow progressively worse, affecting balance and gait.

Recently, researchers at Baylor College of Medicine in Houston and Emory University School of Medicine in Atlanta found the mechanism by which gene defect causes the disease. Their report appeared in a recent issue of the journal Neuron.

Gene associated with fragile X syndrome in children

"They are two different diseases, but they are related to one gene," said Juan Botas, Ph.D., associate professor of molecular and human genetics at BCM. Fragile X syndrome is the most common inherited form of mental retardation. It occurs in one in 4,000 males and one in 6,000 females.

The interplay of two proteins that bind to messenger RNA, a molecule that mediates translation of the information encoded in genes into proteins, triggers the appearance of fragile X-associated tremor/ataxia syndrome (FTAX), a late-life disorder associated with the gene that causes fragile X syndrome in children, according to the report.

Occurrence depends on trinucleotide repeats

The ways in which the two disorders occur differ. In both, it begins with too many repeats of a part of the FMR1 gene. In both, the gene FMR1 contains too many repeats of the trinucleotide sequence CGG. Such sequences usually are part of a code critical in telling a cell to make a particular protein. When these repeats occur, they can sometimes cause a defective protein. The more repeats, the more likely this is to occur.

Individuals with fragile X syndrome have more than 200 repeats, causing the person to lack the fragile X mental retardation protein (FMRP) encoded by the gene. Those who develop fragile X-associated tremor/ataxia syndrome later in life have a "premutation" set of repeats of CGG totaling between 60 and 200.

These individuals make the FMR protein and do not develop fragile X syndrome. Previously, it was thought that 60-200 repeats had no effect on premutation carrier individuals. Now it appears that it does affect a subset of carriers, although it is unclear how many.

People with fragile X-associated tremors/ataxia syndrome suffer from tremor that becomes more severe over time.

Abnormal protein links grandfathers, grandchildren

They have difficulty with walking and balance. Their disease can progress slowly over years until they have difficulty carrying out the activities of daily life. It is found in the grandfathers of children with fragile X syndrome, and it often begins when people are in the 50s and 60s. Most of those with the disease are men.

Researchers noticed that people with the fragile X-associated tremor/ataxia syndrome have higher than normal levels of messenger RNA. Messenger RNA or mRNA takes the protein’s blueprint from the DNA in the cell nucleus to the protein-manufacturing ribosome in the cytoplasm (the jelly-like material that fills the cell’s interior).

Two proteins

Studying fruit flies, Botas and his colleagues found two RNA-binding proteins hnRNP A2/B1 and CUGBP1 that are involved in the new disease. RNA-binding proteins control the metabolism of mRNA. However, these RNA-binding proteins tend to bind to CGG repeats. When there are too many CGG repeats, too many molecules of these proteins are bound to the repeats, preventing them from fulfilling their normal function of controlling mRNA metabolism.

When Botas and his colleagues created a fly with too many CGG repeats, the fly developed the neurodegenerative disease. However, when they developed a fly that made more than the normal amount of the RNA-binding proteins, the disease was much less severe.

Others who contributed to the work include Drs. Oyinkan A. Sofola, Maria de Haro and David L. Nelson, all of BCM, and Peng Jin, Yunlong Qin, Ranhui Duan and Huijie Liu, all of Emory University School of Medicine.

Funding for this research came from the National Institutes of Health, the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center and the BCM-Emory Fragile X Research Center.

View the full paper RNA-Binding Proteins hnRNP A2/B1 and CUGBP1 Suppress Fragile X CGG Premutation Repeat-Induced Neurodegeneration in a Drosophila Model of FXTAS. An abstract can be found at http://www.neuron.org/content/article/abstract?uid=PIIS0896627307005429&highlight=botas