Reduction of the DM-associated homeo domain protein (DMAHP) mRNA in different brain areas of myotonic dystrophy patients

Gennarelli, Massimo; Pavoni, M.; Amicucci, Paola; Angelini, C.; Menegazzo, E.; Zelano, Giovanni; Novelli, Giuseppe; Dallapiccola, Bruno

doi:10.1016/s0960-8966(99)00003-6

Cited by 18 publications

(11 citation statements)

References 19 publications

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“…The CTG expansion in the DMPK 3′ UTR are located immediately upstream of the SIX5 promoter region and were shown to lower SIX5 expression (Gennarelli et al 1999;Inukai et al 2000;Klesert et al 1997;Thornton et al 1997). Six5 is a transcription factor required for eye development in Drosophila, and the mouse homologue is implicated in distal limb muscle development (Harris et al 2000).…”

Section: Loss Of Function Of Surrounding Genesmentioning

confidence: 99%

Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy

Kuyumcu-Martinez

Cooper

2006

Alternative Splicing and Disease

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Myotonic dystrophy (DM), the most common form of adult onset muscular dystrophy, affects skeletal muscle, heart, and the central nervous system (CNS). Mortality results primarily from muscle wasting and cardiac arrhythmias. There are two forms of the disease: DM 1 and DM 2. DM 1, which constitutes 98% of cases, is caused by a CTG expansion in the 3′ untranslated region (UTR) of the DMPK gene. DM 2 is caused by a CCTG expansion in the first intron of the ZNF9 gene. RNA containing CUG-or CCUG-expanded repeats are transcribed but are retained in the nucleus in foci. Disease pathogenesis results primarily from a gain of function of the expanded RNAs, which alter developmentally regulated alternative splicing as well as pathways of muscle differentiation. The toxic RNA has been implicated in sequestration of splicing regulators and transcription factors thereby causing specific symptoms of the disease. Here we review the proposed mechanisms for the toxic effects of the expanded repeats and discuss the molecular mechanisms of splicing misregulation and disease pathogenesis.

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Section: Loss Of Function Of Surrounding Genesmentioning

confidence: 99%

Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy

Kuyumcu-Martinez

Cooper

2006

Alternative Splicing and Disease

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“…In addition to inducing silencing of mRNAs containing complementary repeats by an RNAi mechanism, toxic repeat mRNAs may also initiate epigenetic changes that result in heterochromatinization in their own vicinity (Figure 3). This phenomenon, reviewed recently by Kumari and Usdin,68 may explain the DNA methylation and silencing of the FMR1 gene in Fragile X syndrome, as well as reduced expression of genes adjacent to those encoding the toxic RNA in DM1 69–71…”

Section: Direct Effects Mediated Through Interaction With Cellular Famentioning

confidence: 96%

Repeat expansion diseases: when a good RNA turns bad

Dickson

Wilusz

2010

WIREs RNA

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An increasing number of dominantly inherited diseases have now been linked with expansion of short repeats within specific genes. Although some of these expansions affect protein function or result in haploinsufficiency, a significant portion cause pathogenesis through production of toxic RNA molecules that alter cellular metabolism. In this review, we examine the criteria that influence toxicity of these mutant RNAs and discuss new developments in therapeutic approaches.

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“…A second mechanism proposed to explain the pathogenesis of DM1 is based on the effect exerted by CTG expanded repeats on chromatin structure (Otten & Tapscott, 1995), which in turn might lead to partial silencing of neighboring DMWD (Dystrophia myotonica-containing WD repeat motif) and SIX5 (Sine oculis homeobox homolog 5) genes (Alwazzan et al, 1999;Klesert et al, 1997;Sarkar et al, 2000). This hypothesis is supported by the fact that DMWD expression levels are reported as decreased in repeat expansion-bearing patients (Alwazzan et al, 1998;Gennarelli et al, 1999). Moreover, mutant analysis in Drosophila has shown that D-Six4, the closest Six5 homolog in flies, is required for normal development of gonad muscle and mesodermal components.…”

Section: Rna-mediated Mechanisms Of Pathogenesismentioning

confidence: 98%