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Expanded RNA repeat diseases

The expansion of RNA repeats is the cause for neurodegenerative disorders. Abnormal RNA-protein interactions disrupt the physiological functions of proteins.

Many transcripts contain short tandem repeats (STRs). Mutant RNA transcripts can trigger pathological effects when a critical repeat length is reached. In some diseases, abnormal RNA-protein interactions occur, disrupting the physiological functions of bound proteins. These diseases include dominantly inherited disorders associated with long repeat expansions in the non-coding or coding regions of individual genes. 

Interaction between RNA-binding proteins and mutant RNA often results in the immobilization of these proteins in specific structures known as RNA foci. RNA foci are the pathogenic hallmarks of this type of disease.

Studies of proteins bound to CUG repeats in myotonic dystrophy type 1 (DM1) resulted in developing the "RNA gain-of-function" model. The model states that expanded repeats sequester RNA-binding proteins from their normal function.

Proteins trapped by other repeats are well studied now. The RNA repetitions list includes CUG, CAG, CGG, CCUG, AUUCA, and GGGGCC repeats.

Alternative splicing of specific pre-mRNAs is affected by abnormal RNA-protein interactions. Abnormal RNA-protein interactions alter the use of alternative polyadenylation sites of several mRNAs. Changes in nuclear transport and export affect translation, induce nucleolar stress, and dysregulate miRNA processing. Structures formed by expanded repeats appear to trigger protein recruitment.

Mutant transcripts encoded by specific nucleic acid sequences present in the expanded region can adopt stable in-vitro hairpin or G-quadruplex structures. This phenomenon is also known as "RNA-mediated toxicity" in these disorders.

However, many unanswered questions remain regarding the disease-causing molecular mechanism. Molecular probes allowing the study of proteins recruited to RNA foci may help to elucidate these mechanisms, possibly leading to new therapeutic drugs to treat these disorders.

A CTG repeat expansion causes myotonic dystrophy type I (DM1), leading to defects in developmentally regulated alternative splicing. The repeat expansion occurs within the 3’-UTR of the DMPK gene. RNA foci formed by the expanded CUG repeat in the nucleus sequester the muscle-blind-like (MBNL) protein family of splicing factors and induce upregulation of CELF1 through PKC-mediated phosphorylation and altered microRNA regulation.

In 2010, Todd & Paulson reviewed a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. 

Mechanisms discussed in the review include

1. Transcriptional alterations, 

2. Generation of antisense transcripts, 

3. Sequestration of mRNA-associated protein complexes leading to aberrant mRNA splicing and processing,

4. Alterations in cellular processes, 

5. Activation of abnormal signaling cascades and failure of protein quality control pathways.

Antisense oligonucleotides are a promising therapeutic approach for diseases caused by expanded RNA repeats. In particular, antisense oligonucleotides stabilized with chemical modifications such as bridged nucleic acids (BNAs) and phosphorothioates allow the design of gapmers useful for RNA targeting therapeutics.

Table 1 : Disease causing repeats




Normal Repeat

Disease-causing repeat

CNS Phenotype

Myotonic Dystrophy Type 1 (DM1)





50~1500: Adult onset DM1
~1500+: Congenital DM1

Adult onset: Neuropsychiatric symptoms, executive dysfunction

Congenital DM1: mental retardation in>50%.

Myotonic Dystrophy Type 2 (DM2)


Intron 1 of ZNF9


Up to 30


Neuropsychiatric symptoms common

No congenital onset or mental retardation

Fragile X Tremor Ataxia Syndrome (FXTAS)


5′UTR of FMR1



55–200; incomplete penetrance at all repeat lengths.

Late onset

Cerebellar ataxia, action tremor, dementia Parkinsonism.

Neuropsychiatric symptoms in females.

Spinocerebellar ataxia Type 3 (SCA 3)


Exon 10 of ATXN3


Up to 44

~45–51: reduced penetrance
~52–86: Fully penetrant


Parkinsonism, dystonia

dementia uncommon

Spinocerebellar Ataxia Type 8 (SCA8)


5′UTR of KLH1



71>1300; incomplete penetrance at all repeat lengths

Cerebellar Ataxia

dementia uncommon

Spinocerebellar Ataxia Type 10 (SCA10)


3′UTR of E46L




Cerebellar ataxia
cognitive decline

Spinocerebellar Ataxia Type 12 (SCA12)


5′UTR/promoter of PPP2R2B


Up to 32


Action tremor

Cerebellar ataxia
dementia uncommon

Huntington’s Disease Like 2 (HDL-2)


3′UTR of JPH-3




Clinically similar to Huntington’s Disease

(Source: Todd & Paulson)


ORF = Open Reading Frame; UTR = Untranslated Region; DMPK = Dystrophin Myotonica Protein Kinase; ZNF9 = Zinc Finger 9; FMR1 = Fragile X Mental Retardation gene 1; ATXN3 = Ataxin 3; KLH1 = Kelch-Like 1; PPP2R2B = protein phosphatase 2, regulatory subunit B, beta isoform.


CELF1: CUGBP Elav-like family member 1 [UniProtKB]

Ciesiolka A, Jazurek M, Drazkowska K, Krzyzosiak WJ. Structural Characteristics of Simple RNA Repeats Associated with Disease and their Deleterious Protein Interactions. Front Cell Neurosci. 2017 Apr 11;11:97. [PMC]

Magdalena Jazurek, Adam Ciesiolka, Julia Starega-Roslan, Katarzyna Bilinska and Wlodzimierz J. Krzyzosiak; SURVEY AND SUMMARY. Identifying proteins that bind to specific RNAs - focus on simple repeat expansion diseases. Nucleic Acids Research, 2016, Vol. 44, No. 19. 9050-9070.

Konieczny P, Stepniak-Konieczna E, Sobczak K. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 2014;42(17):10873-87. [PMC]

Manning KS, Rao AN, Castro M, Cooper TA. BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells. ACS Chem Biol. 2017 Oct 20;12(10):2503-2509. [PMC]

Todd PK, Paulson HL. RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol. 2010 Mar;67(3):291-300.  [PMC]

M. J. Walsh, J. Cooper-Knock, J. E. Dodd, M. J. Stopford, S. R. Mihaylov, J. Kirby, P. J. Shaw and G. M. Hautbergue;  Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathology and Applied Neurobiology (2015), 41, 109–134. [PMC]



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