ASFMR1 splice variant: A predictor of fragile X-associated tremor/ataxia syndrome

Padmaja Vittal; Shrikant Pandya; Kevin Sharp; Elizabeth Berry-Kravis; Lili Zhou; Bichun Ouyang; Jonathan Jackson; Deborah A Hall

doi:10.1212/NXG.0000000000000246

ASFMR1 splice variant: A predictor of fragile X-associated tremor/ataxia syndrome

Neurol Genet. 2018 Jul 27;4(4):e246. doi: 10.1212/NXG.0000000000000246. eCollection 2018 Aug.

Authors

Padmaja Vittal¹, Shrikant Pandya¹, Kevin Sharp¹, Elizabeth Berry-Kravis¹, Lili Zhou¹, Bichun Ouyang¹, Jonathan Jackson¹, Deborah A Hall¹

Affiliation

¹ Department of Neurosciences (P.V.), Northwestern Medicine Regional Medical Group, Winfield, IL; the Department of Bioengineering (S.P.), University of Illinois at Chicago; the Department of Pediatrics, Neurological Sciences, Biochemistry (K.S., E.B.-K., L.Z., J.J.), and the Department of Neurological Sciences (B.O., D.A.H.), Rush University Medical Center, Chicago, IL.

Abstract

Objective: To explore the association of a splice variant of the antisense fragile X mental retardation 1 (ASFMR1) gene, loss of fragile X mental retardation 1 (FMR1) AGG interspersions and FMR1 CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).

Methods: Premutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression of ASFMR1 transcript/splice variant 2 (ASFMR1-TV2), nonspliced ASFMR1, total ASFMR1, and FMR1 messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.

Results: Premutation men and women both with and without FXTAS had higher ASFMR1-TV2 levels compared with NC men and women (n = 135,135, p < 0.0001), and ASFMR1-TV2 had good discriminating power for FXTAS compared with NCs 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 compared with NC and PMC (combined).

Conclusions: This study found elevated levels of ASFMR1-TV2 and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.