Fragile X syndrome This page contains tooltip text
Fragile X syndrome (FMR1 gene, OMIM +309550) is the most common inherited form of cognitive impairment, also displaying a broad spectrum of emotional and behavioral involvement. The promoter region of full mutation forms of the FMR1 gene (> 200 CGG repeats) is generally hypermethylated and transcriptionally silent, resulting in little or no FMR1 mRNA protein (FMRP). FMRP is an mRNA transport protein and a negative regulator of translation for messages that are utilized in synaptic plasticity. Thus, fragile X syndrome is intrinsically a protein-deficiency syndrome. Fragile X syndrome is also an important genetic basis of autism, with over 50% of boys with fragile X syndrome demonstrating features of autism or autism spectrum disorders. Moreover, approximately 2 to 6% of children with autism have fragile X syndrome.
The phenotype of fragile X syndrome includes hyperactivity, attention problems, anxiety, sensory integration problems leading to tactile defensiveness, unusual hand mannerisms, such as hand flapping, shyness, and poor eye contact. Only 25% of girls with the full mutation have cognitive impairment, but the remaining individuals have learning disabilities, attention problems, shyness, and anxiety typical for the syndrome. Approximately 85% of the males with a full mutation have cognitive impairment, and those without MR still have learning disabilities and social deficits, typically with attention deficit hyperactivity disorder (ADHD). High functioning males with fragile X syndrome often have a lack of FMR1 promoter methylation, although their FMRP levels are still low. These individuals represent an interesting subgroup because their mRNA levels are often elevated along with lowered FMRP levels. This potential mixed phenotype is further explored in Project 4.
Current research on Fragile X syndrome
The focus of our current molecular research is the regulation of expression of the gene at the transcriptional and translational levels, since reduced FMRP levels arise through both transcriptional silencing and reduced efficiency of translation of the expanded-CGG-repeat mRNA. Our work in this area includes:
- Identification of sequence elements within the FMR1 5'UTR that contribute to increased transcriptional activity with increasing CGG repeat length. Attenuation of this increase is a potential approach to targeted therapies for FXTAS.2
- Studies of the mechanism by which translation is impaired by the expanded CGG repeat in RNA. Improved translation from expanded-repeat mRNA would, in principle, supply more protein in cases of fragile X syndrome.
- Further definition of the relationship between epigenetic modifications and transcriptional activity of FMR1 alleles with full mutation expanded CGG repeats.