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Fragile X Syndrome Fragile X syndrome is the most common cause of inherited cognitive deficit (1:4,000 males in the general population); it is associated with a wide range of impairments, from mild learning disabilities to severe mental retardation. Fragile X syndrome is also characterized by a number of physical and behavioral abnormalities, which include among others attentional difficulties and autistic behavior. In most cases, Fragile X syndrome is associated with an unstable expansion of a CGG trinucleotide repeat within the 5’ UTR region of the translational regulator FMR1. Based on the size of this expansion, alleles are classified as normal (5-40 repeats), intermediate or gray zone (41-60 repeats), premutation (61-199 repeats), or full mutation (200-2,000 repeats). Normal alleles are stably transmitted to the next generation, while premutated alleles tend to expand to the full mutation (typically when transmitted from a female). Full mutation-size expansions are regularly associated with hypermethylation, gene silencing, and the Fragile X phenotype. As an X-linked disorder, the severity of the Fragile X phenotype is greater in males. Premutation alleles appear to be linked to other phenotypical manifestations; one of the most severe, the Fragile X tremor ataxia syndrome (FXTAS), affects predominantly older (>50 years) males and includes gait ataxia, intention tremor, cognitive impairment, and other neurologic manifestations. Although marked deficit of the FMR1 product, the Fragile X Mental Retardation Protein (FMRP), is seen in males with the characteristic severe cognitive and behavioral manifestations of Fragile X syndrome, FMRP deficiency per se does not explain the phenotypical variability of the disorder.

Research Projects

Gene Expression and Genetic Mental Retardation