Class Year



Fragile X syndrome, mental retardation


Fragile X syndrome is the most common form of inherited mental retardation, and afflicts 1 in 1250 males and 1 in 2500 females. The symptoms include connective tissue displasia, mental retardation, and macroorchidism (enlarged testis). My lab discovered that the most common forms of this disorder are caused by the expansion of CGG tri-nucleotide repeats on the X chromosome at the FMR-1 gene locus; an excess of 200 repeats in diseased individuals suppresses the translation of FMR-1. The CGG repeat expansion leads to hyper-methylation of a CpG island distal to the repeat, leading to transcriptional repression of FMR-1. This gene silencing is also aided by RNA interference and de-acetylation of histones H3 and H4. The FMR-1 gene codes for fragile X mental retardation protein (FMRP), which plays a functional role in protein translation in neurons. FMRP selectively binds to specific mRNAs essential to development of the brain and other parts of the body, and plays a major role in shuttling its ligands from the nucleoplasm to the dendritic cytoplasm. FMRP knockout mice models demonstrate abnormal dendritic spine growth, suggesting altered synaptic plasticity, which may be responsible for the fragile X phenotype. Elucidating the fragile X mechanism of pathogenesis can aid the development of possible treatments to the world’s leading cause of mental retardation.


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