Neuroanatomical effect of FMR1 gene mRNA in premutation carriers of Fragile X syndrome

Fragile X syndrome (FraX) is associated with an expansion of CGG triplet repeats (Trs). People most affected by FraX have > 200 CGG Trs with methylation of the Fragile X Mental Retardation gene (FMR-1) and subsequent loss of FMR-1 protein (FMRP) production. Clinically unaffected 'premutation' FraX carriers have 50-200 CGG Trs, an unmethylated FMR-1 gene and normal FMRP production. It was previously assumed that Tr expansion of < 200 has no biological effect. Nonetheless, we recently reported that male carriers of FraX (NTMs) have structural abnormalities in brain anatomy. Tassone et al. (2000) found that relative levels of leukocyte FMR-1 mRNA were elevated in a sample of NTMs. Thus, in this study, we related FMR-I mRNA to brain anatomy in 17 NTMs using MRI. mRNA levels were calculated using previously published methods (Tassone et al., 2000) and neuroimaging data were analysed with SPM99. We found that grey matter volume was significantly (P=> 0.001) positively related to mRNA levels in cerebellum, bilateral lingual and temporal occipital cortices, left cuneus and right insula, overlapping with brain regions that we previously reported to differ significantly between NTMs and controls. This is, to our best knowledge, the first study to demonstrate a relationship between mRNA and brain anatomy implicated in higher cognitive function and behaviour in humans.