(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders

Abstract

Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5′ UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.

The polyG diseases: a new disease entity

“…For example, offspring of FXTAS patients can be unaffected or suffer from FXS [ 5 ]. Unexpectedly, males carrying large CGG repeat expansions (up to 300) in NOTCH2NLC seem to be asymptomatic, though NOTCH2NLC mRNA levels decrease as a consequence of hypermethylation around the CGG repeats, displaying a strikingly different prognosis in contrast to FXS patients with full mutation alleles of FMR1 [ 133 ]. However, these individuals may have children with NIID if the repeat number is contracted during spermatogenesis [ 20 ].…”

Nucleic Acid Thermodynamics Derived from Mechanical Unzipping Experiments

“…For example, RNAs and proteins often become trapped in non-productive, misfolded structures [ 3 , 13 , 14 , 15 , 16 , 17 ]. Such structures have been related to the development of many phenotype diseases such as Huntington’s disease, fragile X-associated tremor ataxia syndrome, myotonic dystrophies, and spinocerebellar ataxias, among others [ 18 , 19 , 20 ]. By monitoring one molecule at a time, single-molecule techniques allow for the characterization of these structures, which go undetected in bulk assays.…”

Non-canonical DNA/RNA structures associated with the pathogenesis of Fragile X-associated tremor/ataxia syndrome and Fragile X syndrome

“…In model systems, hyperexpression of riboCGG repeats in the PM range leads to defects in cell development and cell toxicity ( Hagerman, 2012 ; Hagerman et al, 2018 ; Bhat et al, 2021 ). Unlike FM alleles, PM alleles alter RNA-processing mechanisms, which may be related to unusual secondary structures formed by DNA strands and RNA containing CGG and antisense CCG repeats ( Zhao and Usdin, 2021 ). Such unusual secondary structures can potentially impede translation within the PM range through an obscure mechanism ( Zhao and Usdin, 2021 ).…”

“…Unlike FM alleles, PM alleles alter RNA-processing mechanisms, which may be related to unusual secondary structures formed by DNA strands and RNA containing CGG and antisense CCG repeats ( Zhao and Usdin, 2021 ). Such unusual secondary structures can potentially impede translation within the PM range through an obscure mechanism ( Zhao and Usdin, 2021 ). In addition, such secondary structures can sequester specific proteins from their normal biological functions and/or undergo repeat-associated non-AUG (RAN) translation from both sense and antisense strands into toxic homopolymeric peptides ( Todd et al, 2013 ).…”

“…Similarly, in mESCs derived from FX PM mice, the point mutation D1185N in the endonuclease domain of MLH3 precludes repeat expansion, suggesting its importance in this process ( Hayward et al, 2020 ). In addition to MutSβ (an MSH2 and MSH3 heterodimer) and MutSγ (an MSH2 and MSH6 heterodimer) ( López Castel et al, 2010 ; Zhao et al, 2015 ; Zhao et al, 2016 ), three other mammalian protein complexes, MutSα, MutLα, and MutLβ, play important roles in expansion ( Figure 3B ) ( López Castel et al, 2010 ; Miller et al, 2020 ; Zhao and Usdin, 2021 ). Although these studies have suggested that the MMR pathway plays a role in repeat expansion, the mechanism by which MMR substrates are generated remains unclear.…”