TY - JOUR
T1 - Abnormal splicing of NEDD4 in myotonic dystrophy type 2
T2 - Possible link to statin adverse reactions
AU - Screen, Mark
AU - Jonson, Per Harald
AU - Raheem, Olayinka
AU - Palmio, Johanna
AU - Laaksonen, Reijo
AU - Lehtimäki, Terho
AU - Sirito, Mario
AU - Krahe, Ralf
AU - Hackman, Peter
AU - Udd, Bjarne
N1 - Funding Information:
Supported by Folkhälsan Research Foundation , University of Helsinki, National Doctoral Program of Musculoskeletal Disorders and Biomaterials , Liv och Hälsa Foundation , Vasa Central Hospital District Medical Research funds Finnish Foundation of Cardiovascular Research (T.L.), Pirkanmaa Hospital District grant 9N035 (T.L.), Tampere Tuberculosis Foundation (T.L.), Emil Aaltonen Foundation (T.L.), NIH grant AR48171 (R.K.), a Muscular Dystrophy Association grant (R.K.), and a Kleberg Foundation grant (R.K.).
PY - 2014/8
Y1 - 2014/8
N2 - Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n repeat expansion in intron 1 of CNBP. Transcription of the repeats causes a toxic RNA gain of function involving their accumulation in ribonuclear foci. This leads to sequestration of splicing factors and alters pre-mRNA splicing in a range of downstream effector genes, which is thought to contribute to the diverse DM2 clinical features. Hyperlipidemia is frequent in DM2 patients, but the treatment is problematic because of an increased risk of statin-induced adverse reactions. Hypothesizing that shared pathways lead to the increased risk, we compared the skeletal muscle expression profiles of DM2 patients and controls with patients with hyperlipidemia on statin therapy. Neural precursor cell expressed, developmentally downregulated-4 (NEDD4), an ubiquitin ligase, was one of the dysregulated genes identified in DM2 patients and patients with statin-treated hyperlipidemia. In DM2 muscle, NEDD4 mRNA was abnormally spliced, leading to aberrant NEDD4 proteins. NEDD4 was down-regulated in persons taking statins, and simvastatin treatment of C2C12 cells suppressed NEDD4 transcription. Phosphatase and tensin homologue (PTEN), an established NEDD4 target, was increased and accumulated in highly atrophic DM2 muscle fibers. PTEN ubiquitination was reduced in DM2 myofibers, suggesting that the NEDD4-PTEN pathway is dysregulated in DM2 skeletal muscle. Thus, this pathway may contribute to the increased risk of statin-adverse reactions in patients with DM2.
AB - Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n repeat expansion in intron 1 of CNBP. Transcription of the repeats causes a toxic RNA gain of function involving their accumulation in ribonuclear foci. This leads to sequestration of splicing factors and alters pre-mRNA splicing in a range of downstream effector genes, which is thought to contribute to the diverse DM2 clinical features. Hyperlipidemia is frequent in DM2 patients, but the treatment is problematic because of an increased risk of statin-induced adverse reactions. Hypothesizing that shared pathways lead to the increased risk, we compared the skeletal muscle expression profiles of DM2 patients and controls with patients with hyperlipidemia on statin therapy. Neural precursor cell expressed, developmentally downregulated-4 (NEDD4), an ubiquitin ligase, was one of the dysregulated genes identified in DM2 patients and patients with statin-treated hyperlipidemia. In DM2 muscle, NEDD4 mRNA was abnormally spliced, leading to aberrant NEDD4 proteins. NEDD4 was down-regulated in persons taking statins, and simvastatin treatment of C2C12 cells suppressed NEDD4 transcription. Phosphatase and tensin homologue (PTEN), an established NEDD4 target, was increased and accumulated in highly atrophic DM2 muscle fibers. PTEN ubiquitination was reduced in DM2 myofibers, suggesting that the NEDD4-PTEN pathway is dysregulated in DM2 skeletal muscle. Thus, this pathway may contribute to the increased risk of statin-adverse reactions in patients with DM2.
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U2 - 10.1016/j.ajpath.2014.04.013
DO - 10.1016/j.ajpath.2014.04.013
M3 - Article
C2 - 24907641
AN - SCOPUS:84904678832
SN - 0002-9440
VL - 184
SP - 2322
EP - 2332
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 8
ER -