Normal phenotype in two brothers with a full FMR1 mutation

The fragile X syndrome is associated with an expanding CGG repeat in the 5' untranslated region of the first exon of the FMR1 gene. Subsequent methylation of the promoter region inhibits expression of the FMR1 gene. In two clinically normal brothers large, expanded CGG repeats and cytogenetically visible fragile sites were found. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicates that inactivation of the FMR1 gene and not repeat expansion itself results in the fragile X phenotype. We conclude that repeat expansion does not necessarily induce methylation and that methylation is no absolute requirement for the induction of fragile sites.