Length-dependent toxicity of untranslated CUG repeats on Caenorhabditis elegans.
Expansion of CTG repeat within the 3'-untranslated region of the DMPK gene causes the most common neuromuscular disorder, myotonic dystrophy type 1 (DM1), through a RNA trans-dominant mechanism. Here, we explore Caenorhabditis elegans as a model system to investigate the repeat size-dependent toxic effect by expression of green fluorescent protein (GFP) transcripts with various lengths of untranslatable CUG repeats (CUG5, CUG30, CUG83, CUG125, and CUG213) in body wall muscles. CUG213 animals died during embryogenesis or showed retarded growth at larval stages due to defective muscle development. CUG125 animals, although can produce offspring, exhibited uncoordinated muscle function, deviated electropharyngeogram, and an age-dependent abnormality in muscle structure. Most CUG83 animals had normal muscle structure and function as those expressing 30 and shorter repeats. Our results demonstrate for the first time that the in vivo toxicity of CUG repeats is repeat length- and growth-regulated and suggest that expanded CUG repeats are sufficient to cause congenital-like phenotypes in living organisms.
Chen
Kuan-Yu
KY
Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, ROC.
Pan
Huichin
H
Lin
Min-Jon
MJ
Li
Yet-Young
YY
Wang
Li-Chun
LC
Wu
Yi-Chun
YC
Hsiao
Kuang-Ming
KM
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D020506:Untranslated Regions / Q000235:genetics*
D020506:Untranslated Regions