Fragile X Mental Retardation Syndrome Type

In the late 1980s, an interesting new mechanism for gene disruption was discovered as an outgrowth of studies investigating the genetic basis of human degenerative CNS disorders—the triplet repeat mechanism. The essential discovery was that in humans there are repetitive DNA sequences, specifically CGG or similar trinucleotide sequences, that can expand in length (i.e., number of CGG repeats) from generation to generation. In general, once a triplet repeat sequence in or around a gene reaches a critical length, normal expression of the gene product is disrupted. Thus, from one generation to the next a family can go from normal expression of a gene product to loss of that same gene due to triplet repeat expansion.

In another variation of triplet repeat-based disorders, the loss of gene function is not precipitous. For example, in a number of neurodegenerative disorders, the family exhibits anticipation, which refers to a progressive decrease in age-of-onset for the disorder from generation to generation. The decrease in age-of-onset is highly correlated with the length of the triplet repeat expansion.

The exact mechanisms by which triplet repeats disrupt gene expression and gene product function are complex and subject to vigorous investigation at present. If the CGG triplet repeat lies within a coding region of a gene, it can result in the expression of a protein product containing polyglutamine. The presence of the polyglu-tamine stretch can, of course, disrupt the normal function of the protein in which it resides. Alternatively, the expression in cell of polyglutamine itself can be toxic, essentially (or theoretically even directly) resulting in a toxic "gain of function" gene product. Again, the exact mechanisms by which cellular expression of polyglutamine-containing proteins in neurons leads to neurodegeneration is unclear at present and represents an active area of investigation.

There also are a number of ways the presence of triplet repeats has been found to affect gene expression. In myotonic dystrophy, the disorder in which triplet repeats were first identified, the mechanism appears to be due to disruption of the function of upstream regulatory DNA sequences that control expression of a protein kinase referred to as dystrophin protein kinase (a.k.a. DMPK, see Figure 8 of chapter 8), although other genes may also be affected.

For other triplet repeat-based disorders the mechanism is also caused by the loss of gene/protein expression, but through more complex mechanisms (see Box 4). One example in this category is fragile X mental retardation type 1 (14, 16, 17). Fragile X

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