[Molecular and genetic features of fragile X syndrome]

Abstract

The fragile-X syndrome is the most frequent cause of sexlinked mental retardation. In the majority of the cases the mutation responsible for the Martin Bell syndrome is produced when an expansion of the (CGG)n repetition is present in the region 5' of the exón 1 of the gene for X-fragile mental retardation 1 (FMR1), together with a hipermethylation in the CpG promoter region of the gene. The result of this situation is the absence of FMRP protein coded by the gene. The correlation between length of the (CGG)n sequences and of the X-fragile phenotype has permitted a more precise diagnosis of affected and carrier individuals by means of direct DNA analysis. Nevertheless the molecular genetic basis of the instability and expansion of the (CGG)n sequence represents a problem not yet resolved. Two polymorphic microsatellite (AC)n repetitions, FRAXAC1 and FRAXAC2 that flank the FMR-1 gene have been recently described. It has been suggested that some haplotypes of FRAXAC1 and FRAXAC2 could be associated to long (CGG)n repetitions and that these haplotypes would confer more instability to the repeated fragment thus increasing the probability of expansion. It has also been described that the (CGG)n repetition of the FMR-1 gene is interrupted by AGG trinucleotides and that the loss of one AGG would be an important mutational event in the generation of predisposing unstable alleles of of the X-fragile syndrome.