The myotonic dystrophy type 1 triplet repeat sequence induces gross deletions and inversions.
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.
Wojciechowska
Marzena
M
Center for Genome Research Institute of Biosciences and Technology, Texas A & M University System Health Science Center, Texas Medical Center, Houston, Texas 77030, USA.
Bacolla
Albino
A
Larson
Jacquelynn E
JE
Wells
Robert D
RD
D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics; D002872:Chromosome Deletion; D007446:Chromosome Inversion / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics*; D005621:Friedreich Ataxia / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D016296:Mutagenesis / Q000235:genetics; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D020161:Physical Chromosome Mapping; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015183:Restriction Mapping; D017384:Sequence Deletion / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics*
C585517:DMPK protein, human; D004269:DNA, Bacterial; D049452:Green Fluorescent Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases