Study of telomere length in men who carry a fragile X premutation or full mutation allele
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ORIGINAL INVESTIGATION
Study of telomere length in men who carry a fragile X premutation or full mutation allele Igor Albizua1 · Pankaj Chopra1 · Emily G. Allen1 · Weiya He1 · Ashima S. Amin1 · Stephanie L. Sherman1 Received: 4 March 2020 / Accepted: 3 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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.
Introduction Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common monogenic cause of autism spectrum disorder. The gene involved in this disorder, FMR1, is located at q27.3 on the X chromosome; due to its location on the X chromosome, the prevalence of affected males of ~ 1/7000 is higher than affected females, ~ 1/11,000 (Hunter et al. 2014). The mutation that leads to FXS involves an expansion of an unstable trinucleotide repeat (CGG) in the 5′UTR of the FMR1 gene. Normally, the length of this repeat motif is between 5 and 54 repeats, the most frequent alleles being between 28 and 32 repeats. Expansions of this repeat motif to lengths of * Igor Albizua [email protected] 1
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 325.1, Atlant
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