Contribution of the FMR1 gene mutation to human intellectual dysfunction

The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known inherited cause of intellectual dysfunction. The most common mutation occurring in the FMR1 locus involves expansion of a trinucleotide (CGG)n repeat sequence within the promoter region of the gene1. Between 6 and 54 repeats are typically observed in individuals from the general population2. When ≥200 CGG repeats are present, the expanded repeat sequence and an adjacent CpG island are usually hypermethylated, a phenomenon associated with transcriptional silencing of the gene and commonly referred to as the FMR1 full mutation3–5. The intermediate range of repeats (approximately 50 to 200 CGGs), referred to as the premutation, is characterized by the absence of hypermethylation within the promoter region and normal phenotype6,7. Some individuals have a combination of methylated and unmethylated alleles of differing size and are referred to as having mosaic status. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence; in contrast, females with the FMR1 full mutation show a broader range of intelligence, from mental retardation to normal IQ8. The wider spectrum of cognitive functioning in females with the full mutation is likely to be due, in part, to variation in cellular X chromosome inactivation patterns and consequent FMR1 protein (FMRP) production in the brain. Despite differences in severity of intellectual dysfunction, both males and females with the FMR1 full mutation manifest a similar cognitive profile with weakness in the visual-spatial and attentional–organizational domains and relatively preserved verbal abilities9,10. Here, we show that the variance in child IQ predicted by mean parental IQ is decreased in 29 girls with the FMR1 full mutation compared to a non-fragile X group of 50 girls of similar age. We also show that activation status of the FMR1 gene, but not repeat size, is strongly correlated with intellectual function in girls with the full mutation, particularly for cognitive measures which distinguish fragile X from non-fragile X groups. These data indicate that FMR1 activation status is directly associated with the severity of intellectual dysfunction in girls with the fragile X syndrome.