Identification of the gene FMR2, associated with FRAXE mental retardation

Five folate-sensitive fragile sites have been characterized at the molecular level (FRAXA, FRAXE, FRAXF, FRA16A and FRA11B)1–8. Three of them (FRAXA, FRAXE and FRA11B) are associated with clinical problems, and two of the genes (FMR1 in FRAXA2 and CBL2 in FRA11B8) have been identified. All of these fragile sites are associated with (CCG)n/(CGG)n triplet expansions which are hypermethylated beyond a critical size. FRAXE is a rare folate sensitive fragile site only recently recognized9. Its cytogenetic expression was found to involve the amplification of a (CCG)n repeat adjacent to a CpG island5. Normal alleles vary from 6 to 25 copies5. Expansions of greater than 200 copies were found in FRAXE expressing males and their FRAXE associated CpG island was fully methylated5. An association of FRAXE expression with concurrent methylation of the CpG island and mild non-specific mental handicap in males has been reported by several groups10–12. We now report the cloning and characterization of a gene (FMR2) adjacent to FRAXE. Elements of FMR2 were initially identified from sequences deleted from a developmental delayed boy13. We correlate loss of FMR2 expression with (CCG)n expansion at FRAXE, demonstrating that this is a gene associated with the CpG island adjacent to FRAXE and contributes to FRAXE-associated mild mental retardation.