Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island.

Five folate-sensitive fragile sites have been identi-fied at the molecular level to date1–8. Each is characterized by an expanded and methylated trinucleotide repeat of CGG (CCG). Of the three X chromosome sites, FRAXA, FRAXE and FRAXF, the former two are associated with mental retar-dation in their expanded forms. FRAXA expansion results in fragile X syndrome due to down regula-tion of expression of the FMR1 gene, which carries the hypermutable CGG repeat in the 5′ untranslated portion of its first exon9,10. Mild mental retardation without ponsistent physical findings has been found associated with expanded CCG repeats at FRAXE11–13. We have identified a large gene (FMR2) transcribed distally from the CpG island at FRAXE, and down-regulated by repeat expansion and methylation. The gene is novel, expressed in adult brain and placenta, and shows similarity with another human protein, MLLT2, expressed from a gene at chromosome 4q21 involved in translocations found in acute lymphoblastic leukaemia (ALL) cells14,15. Identifi-cation of this gene will facilitate further studies to determine the role of its product in FRAXE associated mental deficiency.