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:

 

targeted therapies - Targeted therapies are those in which a specific feature of the gene, its RNA or protein product, or some feature of its pathogenic mechanism are specifically targeted (blocked or induced) to correct or circumvent the disease process. Examples would include reduction in FMR1 mRNA to treat FXTAS, or inducing the production of more FMRP to improve cognition and behavior for fragile X syndrome.