Abstract
FMR1 gene premutation carriers are at risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. Currently the development of biomarkers and effective treatments in FMR1 premutations is still in its infancy. Recent metabolic studies have shown novel findings in asymptomatic FMR1 premutation carriers and FXTAS, which provide promising insight through identification of potential biomarkers and therapeutic pathways. Here we review the latest advancements of the metabolic alterations found in asymptomatic FMR1 premutation carriers and FXTAS, along with our perspective for future studies in this emerging field.
Highlights
A 55–200 CGG repeat expansion in the 5 UTR of the fragile X mental retardation 1 (FMR1) gene is the hallmark of premutation carriers
Diverse metabolic alterations have been found in FMR1 premutation carriers, including perturbations in the metabolism of carbohydrates, amino acids and derivatives, biogenic amines, fatty acids, structural lipids, and nucleotide
Many of those metabolic alterations can be attributed to mitochondrial dysfunction, such as decreased oxidative phosphorylation (OXPHOS) capacity, changed mitochondrial proteins and altered mitochondrial architecture, which are caused by RNA gain-of function toxicity and repeat-associated non-ATG (RAN) translation (Hukema et al, 2014; Alvarez-Mora et al, 2017; Drozd et al, 2019; Gohel et al, 2019; Nobile et al, 2020)
Summary
A 55–200 CGG repeat expansion in the 5 UTR of the fragile X mental retardation 1 (FMR1) gene is the hallmark of premutation carriers. In FXTAS, the two principal molecular mechanisms are: (1) RNA-gain-of function toxicity (Jin et al, 2003, 2007; Tassone et al, 2004; Sofola et al, 2007; Sellier et al, 2010), which leads to sequestration of various rCGG repeat-binding proteins; and (2) repeat-associated non-ATG (RAN) translation (Todd et al, 2013; Oh et al, 2015; Krans et al, 2016; Sellier et al, 2017), which produces the polyglycine (polyG) peptides toxic to cells As another phenotype of FMR1 premutation, FXPOI is believed to share similar molecular mechanisms with FXTAS based on current evidence, but still needs further research (Elizur et al, 2014, 2019; Buijsen et al, 2016; Man et al, 2017). We begin by describing the basic concepts of metabolism, discuss the specific metabolic alterations associated with FMR1 premutation carriers, and lastly provide an overview of future directions in this field
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