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Section on Neuroadaptation
and Protein Metabolism

Fragile X Syndrome

The products of mutated genes in syndromic forms of autism indicate a link between disrupted synaptic function and the regulation of protein synthesis. Presently, we are studying two such neurodevelopmental disorders: fragile X syndrome (FXS) and tuberous sclerosis complex (TSC).

fxsfig3

FXS is the most common inherited form of cognitive disability in males with an estimated frequency of 1/4000. FXS is usually caused by the expansion of a CGG repeat sequence in the fragile X mental retardation gene (FMR1) on the X chromosome. Normally, the CGG repeat sequence has 4-54 repeats. The fragile X premutation is characterized by a CGG repeat sequence length of 55-200. In this range the repeat sequence is unstable and tends to expand in succeeding generations. When the sequence length expands to greater than 200 repeats, FMR1 is silenced, and, as a consequence, its protein product, fragile X mental retardation protein (FMRP) is absent. This is known as FXS or the full mutation.

Normally, FMRP suppresses protein synthesis, hence in its absence (as in FXS), protein synthesis may be elevated. Our studies address increased rates of cerebral protein synthesis as a core phenotype of FXS in both a mouse model of the disease (Fmr1 KO) and young adult human subjects with the full FXS mutation. In the mouse model, we examine effects of proposed treatments on protein synthesis. We are also measuring rates of protein synthesis in FXS subjects and healthy volunteers to ascertain whether the phenotype seen in the mouse model can be detected in the human disease. Our goal is to establish rates of protein synthesis as a biomarker for FXS, and use this method to test efficacy of potential treatments.