Chapter 24

Fragile-X syndrome is characterized by intellectual deficits, some dysmorphia, and hyperactivity. It is caused by abnormal expansion of a (CGG) ${}_n$ repeat in the $5^{\prime }$ -untranslated region of the $FMR1$ gene and as such results in hypermethylation of CpGs. Considering the role of the $FMR1$ gene in expression of fragile-X syndrome, what is the relationship between hypermethylation and $FMR1$ gene expression?

There are at least eight known progressive neuronal dysfunction diseases in humans that are caused by abnormal numbers of CAG repeats within the coding regions of specific genes. Genes carrying such mutations are typically of the gain-offunction class and often share a common mechanism of progressive pathogenesis. Why are such genes "gain-of-function"? Speculate on why such diseases are probably caused by a common mechanism of pathogenesis.