Triplet repeats in transcripts: structural insights into RNA toxicity

Abstract

Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington ' s disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

“…Consistent with this, we found reduced levels of normal mature Clcn1 and Kcnj2 mRNA. A disruption of mRNA splicing has been shown to cause a decrease in ClC-1 expression in myotonic dystrophy type 1, another trinucleotide repeat disorder (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). We measured elevated levels of aberrant Clcn1 mRNA containing exon 7a in HD muscle, which indicates a similar disruption in Clcn1 pre-mRNA splicing.…”

“…The loss of chloride channels in myotonic dystrophy is thought to be due to an accumulation of RNA with CUG or CCUG repeats in the nucleus that disrupt the function of RNA binding proteins, such as muscleblind-like 1 and 2; consequently, aberrantly spliced Clcn1 mRNA that contains exon 7a is degraded via nonsense-mediated decay (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). We tested for this mechanism in HD interosseous muscle (Fig.…”

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

“…The most recent advances in understanding HD pathogenesis have revealed the coexistence of mutant protein toxicity and detrimental activity of mutant/expanded CAG RNAs (5)(6)(7)(8)(9). Long CAG-trinucleotide repeats form RNA stable hairpin structures (10), with the stem portion presenting protein-binding properties (8,11).…”

“…Long CAG-trinucleotide repeats form RNA stable hairpin structures (10), with the stem portion presenting protein-binding properties (8,11). Abnormal interaction of specific proteins with expanded CAG repeats results in alterations of the normal function of these proteins and consequent perturbations in gene expression and alternative splicing (8,12).…”

“…Long CAG-trinucleotide repeats form RNA stable hairpin structures (10), with the stem portion presenting protein-binding properties (8,11). Abnormal interaction of specific proteins with expanded CAG repeats results in alterations of the normal function of these proteins and consequent perturbations in gene expression and alternative splicing (8,12). In addition, hairpin-like structures in mutant/ expanded transcripts undergo repeat-associated non-ATG (RAN) translation (13), which adds complexity to our understanding of the pathogenic processes in trinucleotide repeat expansion diseases.…”