Fragile X Syndrome FraX

Fragile X syndrome is, after Down's syndrome, the commonest inherited mental deficiency. It develops in one in every 2000 males and one in every 4000 females. In addition to low intelligence, it is often associated with autistic behaviour patterns. As its name indicates, it is due to a deficiency on the X chromosome. This is why it is twice as prevalent in males as in females. One of the intriguing features of the syndrome is that its severity tends to increase and its time of onset decrease over the generations. Although this was at first put down to increasingly effective diagnosis and monitoring it is now known to have a real genetic basis.

The fragile X gene, designated the FMR1 gene (fragile X mental retardation 1), is located on the long arm of the X chromosome (Xq27.3) and contains a CGG repeat in the first exon. The mean repeat number in normal individuals is 29. In individuals with what is known as a 'premutation' there are 55-200 repeats whilst in fully affected individuals the number of copies of the trinucleo-tide is higher than 200 and may be up to 600 and even 1000 and beyond. When the number of repeats exceeds 230 the entire region is methylated, each cytosine in a CG pair coming to bear a methyl group.

The protein encoded by the FRM1 gene is known as FRMP. It is expressed not only in the brain but also in other parts of the body and especially in the testicles. FraX males exhibit macro-orchidism: enlarged testicles. Both males and females also present with connective tissue problems including ear infections, and skeletal problems such as flat feet and double-jointed fingers. Whilst the precise role of FRMP remains unknown there is evidence that it is involved in the regulation of protein synthesis. This is likely to account for the male macro-orchidism mentioned above. High levels of FMR1 mRNA are also found in cerebellar granule cells, in the hippocampus and in the cerebral cortex.

It has been shown that individuals carrying the premutation of up to 200 extra trinucleotides suffer no mental retardation. This is related to the fact that these repeats are free of the cytosine methyla-tion. The earlier onset and increased severity of the syndrome through subsequent generations is due to the trinucleotide repeats getting ever longer. This in some as yet unknown way attracts methylation. This methylation invades a CpG regulatory site near the FMR1 gene and prevents transcription. This is the root cause of the syndrome.

It is interesting to note, finally, that a number of other neurological diseases states, including Friedreich's ataxia, spinobulbar muscular atrophy, myotonic dystrophy, and, as we shall see, Huntington's disease, have also been shown to involve trinucleotide repetitions (see also Section 4.1.1).

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