Abstract for presentation at 11th International Congress of Human Genetics

Grey zone (GZ) alleles are one of the three recognized forms of the X-linked FMR1 gene showing intergenerational instability. They are defined according to the number of CGG repeats in the FMR1 5’ untranslated region. Large CGG expansions (>200) cause fragile X syndrome (FXS), a neurodevelopmental anomaly which results from silencing of the gene and a deficit of FMR1 specific protein. Smaller expansions defined as ‘premutation’ (~55-200) are associated with an increased transcription and late-onset specific phenotypes, including premature ovarian failure in female carriers, and progressive fragile X-associated tremor ataxia syndrome. Those alleles with between ~41-55 repeats in the GZ (or intermediate length) category are relatively poorly defined with regard to both transcriptional and translational activity, and also possible phenotypic effects. Based on a sample of 33 males carrying FMR1 alleles within the GZ range, we demonstrate an increased transcriptional activity relative to that in the common alleles (5-40). This is the first study to provide evidence for a significant linear relationship between FMR1 mRNA levels and CGG repeat number in the GZ alleles defined as either 41-60 range (P<0.0001), or 41-55 range ( P<0.0058). We also find that there is a steep increase in these levels within the GZ range, and this increase slows down within the premutation range. From a piecewise linear regression model the threshold for the onset of the increase of mRNA levels as a function of CGG repeat size has been determined at ~39 repeats (S.E.=3.24), and for the reduction in the rate of this increase at ~ 54 repeats (S.E.=4.27). Our findings address ambiguities associated with the definition and transcription dynamics of the FMR1 gene within the GZ range, and they also imply that there may be specific phenotypes associated with the ‘toxic effect’ of elevated mRNA in GZ carriers to be identified in the future studies.