The Unstable CCTG Repeat Responsible for Myotonic Dystrophy Type 2 Originates from an AluSx Element Insertion into an Early Primate Genome

Tatsuaki Kurosaki,Tohru Matsuura,Shintaroh Ueda,Takafumi Ishida,Koji Abe,Kinji Ohno,Mark A Batzer

doi:10.1371/journal.pone.0038379

Tatsuaki Kurosaki, Tohru Matsuura + Show 5 more

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https://doi.org/10.1371/journal.pone.0038379

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Journal: PLoS ONE	Publication Date: Jun 19, 2012
Citations: 60	License type: CC BY 4.0

Affiliation: The University of Tokyo, Nagoya University

Abstract

Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, ranging from 75–11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3′-end of an AluSx element, flanked by target site duplications (5′-ACTRCCAR-3′or 5′-ACTRCCARTTA-3′), followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s) by which Alu-mediated repeats developed into the large, extremely unstable expansions common to these three disorders.

Highlights

Myotonic dystrophy type 2 (DM2) is an autosomal dominant multi-system disorder
To gain insight into the unstable DM2 repeat expansion mutation, we addressed the evolutionary history of the complex diand tetra-nucleotide repeat configuration of (TG)n(TCTG)n(CCTG)n and the flanking Alu element
We found repetitive elements of a DNA transposon and short interspersed repetitive elements (SINE), namely MER2, AluSx and AluY, located adjacent to the DM2 repeat, in inverse directions to the zinc finger 9 (ZNF9) reading frame (Figure 1A)

Summary

Introduction

Myotonic dystrophy type 2 (DM2) is an autosomal dominant multi-system disorder. It is caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger 9 (ZNF9) gene on chromosome 3q21 [1]. The repeat shows a complex motif with an overall configuration of (TG)n(TCTG)n(CCTG)n. The number of CCTG tracts is less than 30, with repeat interruptions of GCTG and/or TCTG motifs [6], and is stably transmitted from one generation to the [1]. In the expanded allele, only the CCTG tract elongates, and the GCTG and TCTG interruptions disappear from the repeat tract. The sizes of expanded alleles are extremely variable, ranging from 75–11,000 repeats, with a mean of 5,000 repeats. The mechanism(s) underlying this unprecedented instability remains largely unknown, the uninterrupted CCTG repeat is prone to form a stable hairpin/dumbbell

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