Lack of FMR3 expression in a male with non-syndromic mental retardation and a microdeletion immediately distal to FRAXE CCG repeat

Abstract

FRAXE fragile site associated mental retardation (FRAXE MR) belongs to a group of non-syndromic X-linked mental retardation. Two genes, FMR2 and FMR3 (likely a non-coding RNA) are transcribed from the FRAXE CpG island in the opposite directions. While the contribution of the FMR2 gene to FRAXE MR has been demonstrated, the role of the FMR3 gene is not known. We have screened 441 Brazilian mentally handicapped males for CCG repeat expansions in the FMR2 gene and identified a boy with a mutation (c.-414_-357del58) immediately distal to the FRAXE CCG repeat. We have established a skin fibroblast cell line from this patient and tested expression of both FMR2 and FMR3 genes. Reverse transcriptase PCR studies on the FMR2 and FMR3 genes showed that only the FMR3 gene transcription was abolished, suggesting a possible causal relationship between the lack of FMR3 expression and mental retardation in this patient. In the literature, there have been few deletions described near the FRAXE CCG repeat, but none was followed with expression studies. This is the first study showing missing expression in the FMR3 gene with normal FMR2 transcription leading to FRAXE mutation-likely phenotype. The FMR3 gene is likely a non-coding RNA gene. So far all individuals with FRAXE CCG repeat expansions and cytogenetically detectable FRAXE fragile site have both FMR2 and FMR3 gene expression abolished. Although the function of the FMR3 gene is not known, our present study together with previous studies on FRAXE MR suggest that it may play role in the processes underpinning normal learning and memory.