TRINUCLEOTIDE REPEAT AMPLIFICATION AND HYPERMETHYLATION OF A CPG ISLAND IN FRAXE MENTAL-RETARDATION

We have cloned the fragile site FRAXE and demonstrate that individuals with this fragile site possess amplifications of a GCC repeat adjacen t to a CpG island in Xq28 of the human X chromosome. Normal individual s have 6-25 copies of the GCC repeat, whereas mentally retarded, FRAXE -positive individuals have >200 copies and also have methylation at th e CpG island. This situation is similar to that seen at the FRAXA locu s and is another example in which a trinucleotide repeat expansion is associated with a human genetic disorder. In contrast with the fragile X syndrome, the GCC repeat can expand or contract and is equally unst able when passed through the male or female line. These results also h ave implications for the understanding of chromosome fragility.