Article

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: 22.66). 02/2007; 30:575-621. DOI: 10.1146/annurev.neuro.29.051605.113042
Source: PubMed

ABSTRACT 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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    • "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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    • "Polyglutamine diseases are neurodegenerative disorders caused by expansion of CAG trinucleotide repeats encoding polyglutamine tracts in specific genes (Orr and Zoghbi, 2007). The family of polyglutamine diseases includes spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17. "
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    ABSTRACT: Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis.
    Neuron 01/2015; 85(1):88-100. DOI:10.1016/j.neuron.2014.12.031 · 15.98 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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    ABSTRACT: This chapter addresses novel interesting findings of therapeutic potential to target DM1 with small molecule kinase inhibitors and the promises this may provide to this devastating disorder. DM1 is the most common muscular dystrophy in adults and at present has no effective therapy for its treatment. The pathogenesis of this autosomal dominant disorder is mediated by the mutant transcript. DMPK transcripts with expanded CUG repeats (CUG mut) become arrested in the nucleus and form multiple discrete inclusions (foci), and their toxic effects are mediated through at least two antagonistic regulators of alternative splicing: MBNL1 and CUGBP1. Loss of MBNL1 and a gain of CUGBP1 functions result in aberrant splicing of several mRNAs which lead to predominance of embryonic-specific splicing isoforms in adult DM1 tissues. To date, efforts to develop therapeutic strategies for DM1 have mostly been focused on disrupting the toxic nuclear foci by targeting CUG mut with antisense tools. However, the latest reports provide evidence for a novel alternative strategy via targeting protein kinases with small molecule inhibitors. There is reason to envisage such an approach since in DM1 cells CUG mut adversely affect various proteomic elements. As
    Myotonic Dystrophies: Epidemiology, Diagnosis and Therapeutic Challenges, 01/2015; NOVA SCIENCE PUBLISHERS, INC..
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