The RNA-mediated pathogenesis model for the myotonic dystrophies DM1 and DM2 proposes that mutant transcripts from the affected genes sequester a family of double-stranded RNA-binding factors, the muscleblind proteins MBNL1, MBNL2 and MBNL3, in the nucleus. These proteins are homologues of the Drosophila muscleblind proteins that are required for the terminal differentiation of muscle and photoreceptor tissues, and thus nuclear sequestration of the human proteins might impair their normal function in muscle and eye development and maintenance. To examine this model further, we analyzed the expression pattern of the mouse Mbnl1, Mbnl2, and Mbnl3 genes during embryonic development and compared muscleblind gene expression to Dmpk since the RNA pathogenesis model for DM1 requires the coordinate synthesis of mutant Dmpk transcripts and muscleblind proteins. Our studies reveal a striking overlap between the expression of Dmpk and the muscleblind genes during development of the limbs, nervous system and various muscles, including the diaphragm and tongue.
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MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.
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Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, France.
Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease.
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Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy.
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Article Synopsis
- Loss of gene function can sometimes be offset by similar genes, known as paralogs, that have overlapping roles, as seen with the Muscleblind-Like (MBNL) proteins in Myotonic Dystrophy Type 1 (DM1).
- When MBNL1 is lost, MBNL2 levels rise in certain tissues, allowing MBNL2 to take over some functions of MBNL1.
- The study reveals that the increase of MBNL2 is linked to specific changes in its gene splicing, affecting its location and stability, and suggests this compensatory process may play a significant role in DM1-related mechanisms.
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