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. 2018 Aug 22:9:302.
doi: 10.3389/fgene.2018.00302. eCollection 2018.

Assessment of Molecular Measures in Non-FXTAS Male Premutation Carriers

Reem R Al Olaby  1 , Hiu-Tung Tang  1 , Blythe Durbin-Johnson  2 , Andrea Schneider  3   4 , David Hessl  4   5 , Susan M Rivera  5   6 , Flora Tassone  1   3
Affiliations

Assessment of Molecular Measures in Non-FXTAS Male Premutation Carriers

Reem R Al Olaby et al. Front Genet. .

Abstract

Approximately 30-40% of male and 8-16% of female carriers of the Fragile X premutation will develop a neurodegenerative movement disorder characterized by intentional tremor, gait ataxia, autonomic dysfunction, cognitive decline, and Parkinsonism during their lifetime. At the molecular level, premutation carriers have increased expression levels of the FMR1 and the antisense FMR1 (ASFMR1) mRNAs. Both genes undergo alternative splicing giving rise to a number of different transcripts. Alteration in the alternative splicing process might be associated with FXTAS. In this study, we have investigated the correlation between objective measures of movement (balance and tremor using the CATSYS battery) and the expression of both the FMR1 and the ASFMR1 genes. In addition, we investigated whether their expression level and that of the ASFMR1 131 bp splice isoform could distinguish between premutation carriers with FXTAS and non-FXTAS premutation carriers. Confirming previous findings, the expression levels of transcripts at the FMR1 locus positively correlated with the CGG repeat number and significantly differentiated the premutation carriers from the control groups. Furthermore, premutation carriers with and without FXTAS, showed a significant difference in the expression level of the ASFMR1 131 bp splice isoform when compared to age and gender matched controls. However, there was no significant difference in the ASFMR1 131 bp splice isoform expression level when comparing premutation carriers with and without FXTAS. Finally, our results indicate significant group differences in CATSYS dominant hand reaction time and postural sway with eyes closed in premutation carriers without FXTAS compared to controls. In addition, a significant inverse association between the tremor intensity and the expression level of ASFMR1 131 bp splice isoform in premutation carriers compared to controls, was observed, suggesting a potential role in the pathogenesis of FXTAS.

Keywords: ASFMR1; CATSYS; FMR1; FXTAS; premutation; splicing isoforms; transcription.

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Figures

FIGURE 1
FIGURE 1
Plots showing the correlation between the expression level of the ASFMR1 spicing isoform 131 bp mRNA and tremor intensity in the non-dominant hand (A), tremor intensity in the dominant hand (B), and tremor intensity while writing with dominant hand (C) in controls compared to premutations without FXTAS.
FIGURE 2
FIGURE 2
Box plots showing the expression of FMR1 (A), ASFMR1 (B), and ASFMR1 131 bp splicing isoform (C) in premutation carriers compared to controls. Correlation between CGG repeat number and the expression levels of (D) FMR1, (E) ASFMR1, and (F) ASFMR1 131 bp splicing isoform mRNAs.
FIGURE 3
FIGURE 3
Box plots showing differential expression levels of FMR1 (A), ASFMR1 (B) and ASFMR1 131 bp splicing isoform (C) mRNAs in controls compared to non-FXTAS premutation carriers and FXTAS premutation carriers. FMR1, ASFMR1, and ASFMR1 131 bp splicing isoform mRNAs expression levels, as function of the CGG repeat number, are shown in D, E and F respectively.
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