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J. Biol. Chem., Vol. 280, Issue 2, 941-952, January 14, 2005

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The Myotonic Dystrophy Type 1 Triplet Repeat Sequence Induces Gross Deletions and Inversions^*

Marzena Wojciechowska, Albino Bacolla, Jacquelynn E. Larson, and Robert D. Wells

From the Center for Genome Research Institute of Biosciences and Technology, Texas A & M University System Health Science Center, Texas Medical Center, Houston, Texas 77030

The capacity of (CTG·CAG)_n and (GAA·TTC)_n repeat tracts in plasmids to induce mutations in DNA flanking regions was evaluated in Escherichia coli. Long repeats of these sequences are involved in the etiology of myotonic dystrophy type 1 and Friedreich's ataxia, respectively. Long (CTG·CAG)_n (where n = 98 and 175) caused the deletion of most, or all, of the repeats and the flanking GFP gene. Deletions of 0.6–1.8 kbp were found as well as inversions. Shorter repeat tracts (where n = 0 or 17) were essentially inert, as observed for the (GAA·TTC)₁₇₆-containing plasmid. The orientation of the triplet repeat sequence (TRS) relative to the unidirectional origin of replication had a pronounced effect, signaling the participation of replication and/or repair systems. Also, when the TRS was transcribed, the level of deletions was greatly elevated. Under certain conditions, 30–50% of the products contained gross deletions. DNA sequence analyses of the breakpoint junctions in 47 deletions revealed the presence of 1–8-bp direct or inverted homologies in all cases. Also, the presence of non-B folded conformations (i.e. slipped structures, cruciforms, or triplexes) at or near the breakpoints was predicted in all cases. This genetic behavior, which was previously unrecognized for a TRS, may provide the basis for a new type of instability of the myotonic dystrophy protein kinase (DMPK) gene in patients with a full mutation.

Received for publication, September 10, 2004 , and in revised form, October 13, 2004.

^* This work was supported by National Institutes of Health Grants NS37554 and ES11347, the Robert A. Welch Foundation, the Muscular Dystrophy Association, Friedreich's Ataxia Research Alliance, and the Seek-a-Miracle Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Genome Research, Institute of Biosciences and Technology, Texas A & M University System Health Science Center, Texas Medical Center, 2121 W. Holcombe Blvd., Houston, TX 77030. Tel.: 713-677-7651; Fax: 713-677-7689; E-mail: rwells{at}ibt.tamu.edu.

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