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Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene

Nature Genetics volume 16, pages 407–409 (1997)Cite this article

Abstract

Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy, insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene1–5. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5–13 kb in postmortem tissue6,7) and its location in the 3′ untranslated region of the gene that contains it8. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene9,10, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes11. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene12. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in as, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

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Authors and Affiliations

  1. Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA

    Charles A. Thornton, James P. Wymer, Carolyn McClain & Richard T. Moxley III

  2. Division of Neurology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    Zachary Simmons

  3. Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14642, USA

    Richard T. Moxley III

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  1. Charles A. Thornton
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  2. James P. Wymer
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  4. Carolyn McClain
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  5. Richard T. Moxley III
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Thornton, C., Wymer, J., Simmons, Z. et al. Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat Genet 16, 407–409 (1997). https://doi.org/10.1038/ng0897-407

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