Orr HT, Zoghbi HY. Trinucleotide repeat disorders

Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Annual Review of Neuroscience (Impact Factor: 19.32). 02/2007; 30(1):575-621. DOI: 10.1146/annurev.neuro.29.051605.113042
Source: PubMed


The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.

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    • "Huntington disease (HD) is a progressive neurodegenerative disorder characterized by severe movement, cognitive, and behavioral changes caused by a CAG,CTG expansion in the HTT gene (Orr and Zoghbi, 2007). Upon translation, this expansion mutation results in the production of a mutant huntingtin protein (HTT) with an expanded polyGln repeat tract. "
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    ABSTRACT: Huntington disease (HD) is caused by a CAG⋅CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.
    Neuron 11/2015; 88(4):667-677. DOI:10.1016/j.neuron.2015.10.038 · 15.05 Impact Factor
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    • "Polyglutamine (polyQ) expansion causes at least nine inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17, dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA) (Orr and Zoghbi, 2007). Studies of various polyQ disease proteins have shown that expanded polyQ tracts affect the function of the disease proteins, leading to a gain or loss of function (Lim et al., 2008). "
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    ABSTRACT: In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
    Cell Reports 09/2015; 13(1). DOI:10.1016/j.celrep.2015.08.060 · 8.36 Impact Factor
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    • "Patients suffer from myotonia, muscle weakness and wasting, and a variety of other symptoms including cardiac arrhythmias, diabetes, and cataracts. DM1 belongs to a larger group of human neurological disorders associated with expansions of simple repetitive elements within specific genes [2]. This autosomal dominant disease results from the expansion of CTG repeat in the 3'UTR of the DMPK gene and its pathogenesis is mediated, at least in part, by a toxic RNA gainof-function mechanism manifested by nuclear retention of affected DMPK mRNAs which form multiple discrete foci [3] [4] [5]. "
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    DESCRIPTION: Contribution for a book entitled: Myotonic Dystrophies: Epidemiology, Diagnosis and Therapeutic Challenges.
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