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

Xiaonan Zhao,Karen Usdin

doi:10.3390/ijms22179167

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.

Highlights

Repeat expansion diseases (REDs) are a group of human diseases caused by the presence of a large number of repeats in a microsatellite or short tandem repeat (STR) [1]
Numbered amongst these proteins are the splicing factor src-associated in mitosis of 68 kDa (Sam68) [104], and the DiGeorge syndrome critical region gene 8 (DGCR8) protein [84], a double-stranded RNA-binding protein involved in the microRNA-processing pathway
While the ability of the fragile X (FX) repeats to form secondary structures of various sorts has been known for some time, work in recent years has begun to identify ways to target these structures or the downstream consequences of these structures, so as to ameliorate their effects

Summary

Introduction

Repeat expansion diseases (REDs) are a group of human diseases caused by the presence of a large number of repeats in a microsatellite or short tandem repeat (STR) [1]. As with other expansion-prone repeats, the CGG/CCG repeats responsible for the FMR1 disorders form a variety of nucleic acid secondary structures (Figure 1) These structures have the potential to interfere with many biological processes. In this review we will focus primarily on what is known about the DNA and RNA structures formed by the FX repeats themselves and their biological effects in the context of both expansion and disease pathology in the FMR1 disorders. Since the CGG/CCG repeats at the FMR1 locus are bidirectionally transcribed, they can form double R-loops [55] In addition to these inter- and intra-strand structures, there is evidence that even the CGGCCG duplex is atypical, adopting a left-handed Z-DNA conformation as illustrated in Figure 1D [56]

Repeat Expansion

Chromosome Fragility

Concluding Remarks