Genetics

Herbert Lubs' work led to the first chromosomal test for FXS when he noticed a chromosomal constriction, or fragile site, could be observed on the X chromosome of affected males during metaphase6. Later, the loss of the Fragile X Mental Retardation 1 (FMR1) gene, and the subsequent lack of its product, FMRP were determined to be the cause of FXS7.

When looking at pedigrees for FXS, it became apparent that the disease struck individuals with an increasingly greater frequency in the more recent generations, a phenomenon that has become known as the Sherman paradox8,9. The Sherman paradox has to do with the nature of the FXS gene mutation in most cases. In over 95% of FXS cases, there is an expansion of a polymorphic CGG repeat in the 5' UTR of exon 17,1). Normally only 5-50 CGG repeats occur in this region. Persons are said to carry a premutation if they have around 50-200 CGG repeats in this region. The full mutation occurs with >200 CGG repeats. The CGG trinucleotide repeat is remarkably unstable, and individuals with 50-200 of these repeats are classified as having a "premutation" because the FMR1 gene is still translated. The CGG repeat is prone to repeat expansion in humans through a mechanism of abnormal processing during replication. Thus, the more CGG repeats there are, the greater the chances are that offspring will carry the full mutation.

When examining the pedigrees from more than 1,500 females with premutation alleles, the smallest premutation that ever expanded to a full mutation in one generation was 59 CGG repeats11. The chances that the number of CGG repeat will change from parent to offspring can be measured, regardless of whether or not the gene becomes a full mutation. Larger trinucleotide repeats were associated with a greater instability in transmitting the same allele from parent to offspring. In mothers with only 49-54 CGG repeats there were further genetic mutations in 19% of the cases, whereas 80% of mothers with 60-65 CGG repeats had some form of unstable transmission of the trinucleotide repeat11.

Individuals with the full mutation can have thousands of CGG repeats, although any number of repeats in the full mutation category causes hyper-methylation of CpG islands upstream in the gene. This recruits histone deacetlyases that condense the chromosomes, and effectively prevent transcription of FMR1 gene12. As FXS is caused by a hypermethylation sequence of DNA, blocking methyl-binding proteins, such as Mecp2, has been suggested as a potential treatment for FXS13. Downregulating methyl binding proteins has consequences, however, as the loss of Mecp2 has been implicated as a causal factor in Rett 's syndrome, a neurological disorder that is also X linked14.

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