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Human Molecular Genetics, 2001, Vol. 10, No. 23 2717-2726
© 2001 Oxford University Press

Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities

Hervé Seznec, Onnik Agbulut1, Nicolas Sergeant2, Cédric Savouret, Antoine Ghestem2, Nacira Tabti3, Jean-Claude Willer4, Lucie Ourth, Chantal Duros, Edith Brisson, Coralie Fouquet, Gillian Butler-Browne1, André Delacourte2, Claudine Junien and Geneviève Gourdon+

INSERM UR383, Hôpital Necker-Enfants Malades, Université René Descartes Paris V, 149–161 rue de Sèvres, 75743 Paris Cedex 15, France, 1CNRS UM 7000, Faculté de Médecine Pitié-Salpétrière, 105 Boulevard de l’Hôpital, 75013 Paris, France, 2INSERM U422, 1 place de Verdun 59045 Lille Cedex , France, 3INSERM U546, Faculté de Médecine Pitié-Salpétrière, 91 Boulevard de l’Hôpital, 75013 Paris, France and 4Department of Clinical Neurophysiology, Hôpital Pitié-Salpétrière, 47 Boulevard de l’Hôpital, 75013 Paris, France

The autosomal dominant mutation causing myotonic dystrophy (DM1) is a CTG repeat expansion in the 3'-UTR of the DM protein kinase (DMPK) gene. This multisystemic disorder includes myotonia, progressive weakness and wasting of skeletal muscle and extramuscular symptoms such as cataracts, testicular atrophy, endocrine and cognitive dysfunction. The mechanisms underlying its pathogenesis are complex. Recent reports have revealed that DMPK gene haploinsufficiency may account for cardiac conduction defects whereas cataracts may be due to haploinsufficiency of the neighboring gene, the DM-associated homeobox protein (DMAHP or SIX5) gene. Furthermore, mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, consistent with an RNA gain of function. We demonstrated that transgenic mice carrying the CTG expansion in its human DM1 context (>45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats, displayed clinical, histological, molecular and electrophysiological abnormalities in skeletal muscle consistent with those observed in DM1 patients. Like DM1 patients, these transgenic mice show abnormal tau expression in the brain. These results provide further evidence for the RNA trans-dominant effect of the CUG expansion, not only in muscle, but also in brain.

+ To whom correspondence should be addressed. Tel: +33 1 44 49 45 23; Fax: +33 1 47 83 32 06; Email: gourdon@necker.frThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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