Objective: To determine the role of a splice variant of the antisense fragile X mental retardation 1 (ASFMR1) gene, loss of FMR1 AGG interspersions and repeat size as well as to explore their association in fragile X-associated tremor/ataxia syndrome (FXTAS).

Background: FXTAS is an inherited neurodegenerative ataxia, which occurs from a 55-200 CGG repeat expansion (premutation range) in the FMR1 gene1. ASFMR is alternatively spliced and its clinical impact is unclear in FXTAS. The role of AGG interruptions within the FMR1 CGG repeat element is also unclear.

Methods: Premutation carriers with FXTAS, without FXTAS, and normal controls (NC) had a neurological evaluation and collection of skin and blood samples. The published criteria for FXTAS were followed to classify as possible, probable or definite FXTAS participants2. Expression of ASFMR1 transcript/splice variant 2 (ASFMR1-TV2)3, non-spliced ASFMR1, total ASFMR1, and FMR1 mRNA were quantified and compared using ANOVA. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating curve analyses were performed.

Results: Premutation men and women both with and without FXTAS had higher ASFMR1-TV2 levels compared to NC men and women (n=156, p<0.0001) and ASFMR1-TV2 had good discriminating power for FXTAS compared to all others but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men) and elevated ASFMR1-TV2 level (in women) were strongly associated with FXTAS.

Conclusions: This study found elevated levels of ASFMR1-TV2 and loss of AGG interruptions in both men and women with FXTAS. ASFMR splice variants and loss of AGG interspersions may be diagnostic or predictive tools in FXTAS and further studies can help elucidate utility and contribution of these parameters to the mechanism of FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

References: 1. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001; 57:127-130. 2. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003; 72:869-878. 3. Ladd PD, Smith LE, Rabaia NA, et al. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 2007; 16:3174-3187.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/antisense-fmr1-splice-variant-a-predictor-of-fragile-x-associated-tremor-ataxia-syndrome/