DELETION OF ALL CGG REPEATS PLUS FLANKING SEQUENCES IN FMR1 DOES NOT ABOLISH GENE-EXPRESSION

The fragile X syndrome is due to the new class of dynamic mutations. I t is associated with an expansion of a trinucleotide repeat (CGG) in e xon 1 of the fragile X mental retardation gene 1 gene (FMR1). Here we present a fragile X family with an unique female patient who was rende red hemizygous for the FRAXA locus due to a large deletion of one X ch romosome. In addition, the other X had a microdeletion in FMR1. PCR an d sequence analysis revealed that the microdeletion included all CGG r epeats plus 97 bp of flanking sequences, leaving transcription start s ite and translation start site intact. Despite this total lack of CGG repeats in the FMR1 gene, Western blot analysis showed expression of F MRP, and the patient's phenotype was essentially normal. X-inactivatio n studies of the androgen-receptor (AR) locus and haplotype determinat ion of microsatellite markers gave evidence that the deletion probably originated from regression of a fully mutated FMR1 gene. Although the minimal number of CGG repeats hitherto reported in FRAXA is six, and at least four other genes associated with CGG repeats are known, sugge sting an as yet unknown function of these repeats, our study clearly d emonstrates that the absence of CGG repeats does not abolish expressio n of the FMR1 gene in lymphoblastoid cells.