Abstract
Fragile X associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele of 55–200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.
Highlights
The fragile X mental retardation (FMR1) gene consists of 17 exons spanning approximately 38 kb of genomic DNA
It is increasingly recognized that disruption of the splicing process, which is regulated by different splicing factors, can contribute to a number of neurological disorders[19,21,22] including autism spectrum disorder (ASD)[23], Parkinson’s disease24, dementia[25], spinal muscular atrophy (SMA)[26], Prader-Willi syndrome (PWS)27, schizophrenia[28], myotonic d ystrophy[29], amyotrophic lateral sclerosis[30,31] and Alzheimer’s d isease[32]
Of the many FMR1 mRNA isoforms that were demonstrated to exist in both humans and mice[11,14,15,16], Iso10/10b showed the highest levels of expression in premutation samples which, together with the Iso4/4b (Fig. 1), result in truncated proteins that lack the function of the nuclear export signal (NES) and RGG box[15]
Summary
The fragile X mental retardation (FMR1) gene consists of 17 exons spanning approximately 38 kb of genomic DNA. Expansions between 55 and 200 CGG repeats (known as premutation carriers) confer the risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder characterized by intention tremor, gait ataxia, autonomic dysfunction, and P arkinsonism[2]. Alternative splicing (AS) is a regulated process occurring during gene expression that increases protein diversity and represents a powerful evolutionary resource. A differential increase of specific FMR1 mRNA isoforms has been observed in premutation carriers, suggesting their potential functional relevance in the pathology of FXTAS due to RNA toxicity[15,16]. The ASFMR1 exhibits a premutation specific alternative splicing, the Iso131bp (Fig. 1), which is mainly expressed in premutation carriers compared to controls, providing a molecular abnormality potentially associated with F XTAS15,36–38. No studies have been conducted to determine whether altered expression FMR1 and ASFMR1 isoforms are biomarkers of incipient FXTAS, in relation to neurological and neuroanatomical changes
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