Session Information
Date: Wednesday, June 7, 2017
Session Title: Ataxia
Session Time: 1:15pm-2:45pm
Location: Exhibit Hall C
Objective: To evaluate the role of splice patterns of the antisense FMR1 (ASFMR) gene in Fragile X-associated tremor/ataxia syndrome (FXTAS)
Background: FXTAS is an inherited neurodegenerative disorder causing adult-onset ataxia due to 55-199 CGG repeat expansion (premutation range) in the FMR1 gene. ASFMR is a gene transcribed in the reverse direction across the repeat sequence in FMR1, giving an expanded GCC-containing repeat in carriers. ASFMR splice variants have been described but its impact is unclear. Normal FMR1 alleles possess 2-3 AGG interruptions within the CGG repeats; but the association of AGG interspersions to FXTAS has not been studied.
Methods: Premutation carriers with FXTAS (FXTAS), without FXTAS (PMC) and normal controls (NC) were evaluated with the FXTAS Rating Scale (FXTAS-RS); skin and blood samples were collected and CGG length and AGG interspersions were quantified. Relative expression of ASFMR transcript/splice variant 2 (ASFMR-TV2), non-spliced ASFMR, total ASFMR and FMR1 mRNA was quantified using real time PCR. Levels of ASFMR-TV2 in 3 groups were compared using ANOVA. Least absolute shrinkage and selection operator (LASSO) logistic regression was performed with age included to select predictors of FXTAS including ASFMR-TV2, AGG interruptions etc for men and women separately.
Results: Subjects with FXTAS (men, median [IQR]:13.63[15.74]; women, median [IQR]:12.52[29.37]) and PMCs (men, median [IQR]:11.35[20.22]; women, median [IQR]:6.87[8.98]) had higher ASFMR-TV2 compared to NC (men, median [IQR]:1.11[1.42]; women, median [IQR]:0.91 [0.67])(p<0.0001 in men and women). For both men and women, AGG interruptions and ASFMR-TV2 were selected by LASSO regression as predictors of FXTAS. Additionally, CGG for men and ASFMR1 for women were selected as predictors.
Conclusions: This study found significantly elevated levels of ASFMR transcript variant 2 in men and women with FXTAS and a loss of AGG interruptions in premutation carriers with FXTAS. ASFMR splice variants may contribute to the mechanism for FXTAS in premutation carriers and warrants further evaluation.
To cite this abstract in AMA style:
P. Vittal, S. Pandya, K. Sharp, E. Berry-Kravis, L. Zhou, B. Ouyang, J. Jackson, D. Hall. Antisense FMR1 splice variant and loss of AGG interruptions are predictors of Fragile X-associated tremor/ataxia syndrome (FXTAS) [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/antisense-fmr1-splice-variant-and-loss-of-agg-interruptions-are-predictors-of-fragile-x-associated-tremorataxia-syndrome-fxtas/. Accessed June 15, 2025.« Back to 2017 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/antisense-fmr1-splice-variant-and-loss-of-agg-interruptions-are-predictors-of-fragile-x-associated-tremorataxia-syndrome-fxtas/