Examination of the Effect of the Polymorphic CGG Repeat in the FMR1 Gene on Cognitive Performance

Abstract

A CGG repeat sequence located in the 5' untranslated region of the FMR1 gene is polymorphic with respect to size and stability of the repeat during parent-offspring transmission. When expanded to over 200 repeats, the gene is hypermethylated and silenced, leading to fragile X syndrome (FXS). Recently, alleles with large unmethylated repeat tracts (premutations) have been associated with ovarian failure and a late-onset tremor/ataxia syndrome, symptoms unrelated to FXS. To further investigate the phenotype consequence of high repeat alleles, we have analyzed Wechsler adult intelligence scales-III (WAIS-III) measures on 66 males and 217 females with a wide range of repeat sizes. Among females only, we found that FMR1 repeat size and transcript level significantly explained approximately 4% of the variance in the Verbal IQ summary measure, suggesting that this polymorphism is one of many factors that influence variation in cognitive performance. Because of the well established association of increasing repeat size with decreasing age at menopause, we also investigated the reproductive stage and use of hormone replacement therapy (HRT) as a covariate to model verbal intelligence quotient (VIQ). We found that it explained an additional 5% of the variance in VIQ, but did not interact with FMR1 repeat and transcript level.

Language development and fragile X syndrome: Profiles, syndrome‐specificity, and within‐syndrome differences

“…Nevertheless, there is substantial within-syndrome variability in the severity of affectedness, as well as in the precise profile of impairments and psychopathology manifested [Mazzocco, 2000;Kaufmann, 2002;Loesch et al, 2004]. Moreover, there is emerging evidence that even the FMR1 premutation is associated with a distinctive phenotype [Johnston et al, 2001;Aziz et al, 2003;Goodlin-Jones et al, 2004;Moore et al, 2004;Allen et al, 2005;Hessl et al, 2005]. In the next sections, we briefly review those aspects of the phenotype and its variable manifestations that are relevant for understanding the language difficulties of this population.…”

“…Females with the premutation, especially those with larger expansions, are at an elevated risk of depression, obsessive-compulsive disorder, anxiety, and ASD [Goodlin-Jones et al, 2004;Hessl et al, 2005]. The evidence for a cognitive phenotype in premutation females, however, is more equivocal [Steyaert et al, 2003;Moore et al, 2004;Allen et al, 2005]. In large measure, the premutation phenotype results from lower FMRP levels and elevated levels of FMR1 messenger RNA [Allen et al, 2005].…”

“…The evidence for a cognitive phenotype in premutation females, however, is more equivocal [Steyaert et al, 2003;Moore et al, 2004;Allen et al, 2005]. In large measure, the premutation phenotype results from lower FMRP levels and elevated levels of FMR1 messenger RNA [Allen et al, 2005]. Aging premutation carriers, both males and females, are also at Thus, the negative effects of the FMR1 mutation and premutation are clearly developmental in nature, with different symptoms emerging or intensifying at different points in the life course .…”

Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

“…The protocols and consent forms for ascertainment were approved by the Institutional Review Board at Emory University. For more information on study population ascertainment, see Allen et al (2005).…”

“…In 2005 we published a study examining cognition among 66 men and 217 women with varying FMR1 repeat lengths (Allen et al 2005). We reported that women who were carriers of premutation alleles had significantly lower verbal IQ scores compared to non-carriers.…”