Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length

Abstract

Women who carry a fragile X premutation, defined as having 55–200 unmethylated CGG repeats in the 5′ UTR of the X-linked FMR1 gene, have a 20-fold increased risk for primary ovarian insufficiency (FXPOI). We tested the hypothesis that women with a premutation+FXPOI have shorter telomeres than those without FXPOI because they are “biologically older”. Using linear regression, we found that women carrying a premutation (n=172) have shorter telomeres and hence, are “biologically older” than women carrying the normal size allele (n=81). Strikingly, despite having shorter telomeres, age was not statistically associated with their telomere length, in contrast to non-carrier controls. Further, telomere length within premutation carriers was not associated with repeat length but was associated with a diagnosis of FXPOI, although the latter finding may depend on FXPOI age of onset.

Study of telomere length in men who carry a fragile X premutation or full mutation allele

“…We had to focus on those older than 40 years of age due to the later age at diagnosis of male carriers, and therefore, the later age at blood draw. We found a similar pattern as we did for female carriers (Albizua et al 2017). Male carriers had shorter telomeres at younger years and a regression slope that was less than noncarriers, suggesting a different pattern of decline of telomere length with age (Table 3).…”

“…More directly, in a small sample of men with a premutation, Jenkins et al (2008Jenkins et al ( , 2012 found shorter telomere lengths, but this shortening was not exacerbated by a diagnosis of FXTAS or FXTAS plus dementia (see "Introduction"). Furthermore, in our previous study of 172 women who carry a premutation, we found a similar pattern of shorter telomeres among carriers compared with controls (n = 81), suggesting increased biologically aging (Albizua et al 2017). More specifically, we found that premutation carriers had shorter telomere lengths in their younger years compared with noncarriers and the slope of the line across ages was less pronounced than for controls.…”

“…With respect to female premutation carriers, a study in 2017 (Albizua et al 2017) showed data supporting the hypothesis that the FMR1 premutation was associated with accelerated biological aging in women. Briefly, authors found that women carrying a premutation (n = 172) showed shorter telomeres and hence, were "biologically older" than women carrying the normal size allele (n = 81).…”

“…All participants in this study provided a venous blood sample. As previously described in Albizua et al (2017), DNA was extracted using the Gentra Systems, Puregene Genomic DNA purification kit, quantified and stored at 4 °C. Following Meadows et al (1996), we used fluorescent-labeled primers in a PCR reaction that provided us accurate repeat lengths estimations of up to 90 repeats.…”

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

“…Shorter telomeres have been described in PBMCs of PM males compared to controls or FM carriers, regardless of FXTAS or dementia diagnosis [201][202][203]. In PM female carriers, this shortening was also present, although the difference related to control donors was more evident with a FXPOI diagnosis in young individuals [204]. This observation is tentative to be generalized to any type of POI, as another study revealed that peripheral leukocytes from women suffering idiopathic POI (i.e., showing amenorrhea and high levels of FSH before 40 years of age, but without any known genetic and environmental cause of chromosome instability) were significantly shorter than controls [205].…”