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

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Abstract

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5′ UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are “biologically older”, as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are “biologically older” than men carrying the normal size allele in the same age group.

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Acknowledgements

We would like to thank all the participants who made this study possible, along with those who helped with recruitment and data collection. This work was supported by the award (NS091859) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS).

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  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 325.1, Atlanta, GA, 30322, USA

    Igor Albizua, Pankaj Chopra, Emily G. Allen, Weiya He, Ashima S. Amin & Stephanie L. Sherman

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  1. Igor Albizua
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  2. Pankaj Chopra
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  3. Emily G. Allen
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  4. Weiya He
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Correspondence to Igor Albizua.

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Albizua, I., Chopra, P., Allen, E.G. et al. Study of telomere length in men who carry a fragile X premutation or full mutation allele. Hum Genet 139, 1531–1539 (2020). https://doi.org/10.1007/s00439-020-02194-8

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