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

Abstract

Five folate-sensitive fragile sites have been identi-fied at the molecular level to date^1–8. 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 exon^9,10. Mild mental retardation without ponsistent physical findings has been found associated with expanded CCG repeats at FRAXE^11–13. 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) cells^14,15. Identifi-cation of this gene will facilitate further studies to determine the role of its product in FRAXE associated mental deficiency.