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 human X chromosome and is associated with a mild form of mental handicap. Normal individuals have 6-35 copies of the repeat whereas cytogenetically 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 bp cDNA which begins 331 bp distal to the FRAXE site and extends to a region > 170 kb distal in Xq28. The cDNA sequence possesses both a putative 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 analysis, the cDNA detects a 9.5 kb transcript in human brain, placenta and lung. This transcript is present in multiple human brain tissues, but is more abundant in the hippocampus and the amygdala, thus providing possible functional insights. RT-PCR of normal adult brain RNA provides evidence for the existence of the 1495 bp transcript represented by the isolated cDNA.