Abstract
Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3′UTR of the DM protein kinase (DMPK) gene. DMPK transcripts carrying CUG expansions form nuclear foci and affect splicing regulation of various RNA transcripts. Furthermore, bidirectional transcription over the DMPK gene and non-conventional RNA translation of repeated transcripts have been described in DM1. It is clear now that this disease may involve multiple pathogenic pathways including changes in gene expression, RNA stability and splicing regulation, protein translation, and micro–RNA metabolism. We previously generated transgenic mice with 45-kb of the DM1 locus and >300 CTG repeats (DM300 mice). After successive breeding and a high level of CTG repeat instability, we obtained transgenic mice carrying >1,000 CTG (DMSXL mice). Here we described for the first time the expression pattern of the DMPK sense transcripts in DMSXL and human tissues. Interestingly, we also demonstrate that DMPK antisense transcripts are expressed in various DMSXL and human tissues, and that both sense and antisense transcripts accumulate in independent nuclear foci that do not co-localize together. Molecular features of DM1-associated RNA toxicity in DMSXL mice (such as foci accumulation and mild missplicing), were associated with high mortality, growth retardation, and muscle defects (abnormal histopathology, reduced muscle strength, and lower motor performances). We have found that lower levels of IGFBP-3 may contribute to DMSXL growth retardation, while increased proteasome activity may affect muscle function. These data demonstrate that the human DM1 locus carrying very large expansions induced a variety of molecular and physiological defects in transgenic mice, reflecting DM1 to a certain extent. As a result, DMSXL mice provide an animal tool to decipher various aspects of the disease mechanisms. In addition, these mice can be used to test the preclinical impact of systemic therapeutic strategies on molecular and physiological phenotypes.
Highlights
Myotonic dystrophy type I (DM1) is a dominantly inherited disorder, highly variable and associated with multisystemic symptoms
Myotonic dystrophy type 1 (DM1) is caused by the abnormal expansion of a CTG repeat located in the DM protein kinase (DMPK) gene
We described for the first time, the expression pattern of the DMPK sense transcripts in DMSXL and human tissues
Summary
Myotonic dystrophy type I (DM1) is a dominantly inherited disorder, highly variable and associated with multisystemic symptoms. The adult onset form of the condition typically presents distal muscle weakness, myotonia, cardio-respiratory problems, presenile cataracts, hypersomnia, hyperinsulinism, testicular atrophy and early frontal balding in males [1]. The more severe congenital form of DM1 (CDM) is characterized by general hypotonia at birth, respiratory distress, difficulties in sucking and swallowing and facial weakness. Mortality in CDM during the neonatal period has been estimated between 30% and 40% of patients [2]. The genetic mutation causing DM1 is the expansion of an unstable CTG repeat in the 39 untranslated region (39UTR) of a gene encoding a protein kinase (DMPK) [3,4,5]. The normal DMPK gene contains 5–37 CTG repeats in the 39UTR, while all DM1 patients have repeats expanding from 50 to several thousand CTG trinucleotide repeats in CDM. The size of the CTG repeat generally increases from generation to generation in DM1 families [1]
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