A CANDIDATE GENE FOR MILD MENTAL HANDICAP AT THE FRAXE FRAGILE SITE

The cytogenetic expression of the folate sensitive fragile site, FRAXE , is due to the expansion of a GCC repeat in proximal Xq28 of the huma n X chromosome and is associated with a mild form of mental handicap, Normal individuals have 6-35 copies of the repeat whereas cytogenetica lly positive, developmentally delayed males have >200 copies and show methylation of the associated CpG island, Through the use of conserved sequences adjacent to the FRAXE GCC repeat, we have isolated a 1495 b p cDNA which begins 331 bp distal to the FRAXE site and extends to a r egion >170 kb distal in Xq28, The cDNA sequence possesses both a putat ive start of translation and a poly-A tail, The predicted protein has amino acid motifs which share significant homologies with the human AF -4 gene which encodes a putative transcription factor, On northern ana lysis, the cDNA detects a 9.5 kb transcript in human brain, placenta a nd lung, This transcript is present in multiple human brain tissues, b ut is more abundant in the hippocampus and the amygdala, thus providin g possible functional insights, RT-PCR of normal adult brain RNA provi des evidence for the existence of the 1495 bp transcript represented b y the isolated cDNA.