Myotonic dystrophies 1 and 2: complex diseases with complex mechanisms.

Benedikt Schoser,Lubov Timchenko

doi:10.2174/138920210790886844

Abstract

Two multi-system disorders, Myotonic Dystrophies type 1 and type 2 (DM1 and DM2), are complex neuromuscular diseases caused by an accumulation of expanded, non-coding RNAs, containing repetitive CUG and CCUG elements. Similarities of these mutations suggest similar mechanisms for both diseases. The expanded CUGn and CCUGn RNAs mainly target two RNA binding proteins, MBNL1 and CUGBP1, elevating levels of CUGBP1 and reducing levels of MBNL1. These alterations change processing of RNAs that are regulated by these proteins. Whereas overall toxicity of CUGn/CCUGn RNAs on RNA homeostasis in DM cells has been proven, the mechanisms which make these RNAs toxic remain illusive. A current view is that the toxicity of RNA CUGn and CCUGn is associated exclusively with global mis-splicing in DM patients. However, a growing number of new findings show that the expansion of CUGn and CCUGn RNAs mis-regulates several additional pathways in nuclei and cytoplasm of cells from patients with DM1 and DM2. The purpose of this review is to discuss the similarities and differences in the clinical presentation and molecular genetics of both diseases. We will also discuss the complexity of the molecular abnormalities in DM1 and DM2 caused by CUG and CCUG repeats and will summarize the outcomes of the toxicity of CUG and CCUG repeats.

Highlights

Myotonic dystrophies (DMs) are autosomal dominant, multisystem diseases with a common pattern of clinical signs and symptoms such as myotonia, muscular dystrophy, cardiac conduction defects, cataracts, and endocrine disorders
In 1994, a different multisystem disorder was identified with comparable clinical features to DM1 but with missing the DM1 CTG repeat expansion [6,7]
It has been shown that, in DM2 myoblasts, the mutant CCUG RNA is aggregating in nuclei similar to the mutant dystrophia myotonica-protein kinase (DMPK) mRNA in DM1 cells; these aggregates do not appear to contain sequences surrounding CCUG expansion [50]. These findings suggest that the pure CCUG repeats are accumulating in large aggregates after excision of mutant intron 1 of zinc finger protein 9 (ZNF9)

Summary

Introduction

Myotonic dystrophies (DMs) are autosomal dominant, multisystem diseases with a common pattern of clinical signs and symptoms such as myotonia, muscular dystrophy, cardiac conduction defects, cataracts, and endocrine disorders. In Europe, the disease has been termed “Proximal Myotonic Myopathy” (PROMM, OMIM 160900), and in the United States “myotonic dystrophy with no CTG repeat expansion”. After a genetic discovery of the PROMM mutation in 2001 [8], and re-classification [9], the myotonic dystrophies are termed DM1 for the classic type, and DM2 for all other late-onset proximal myotonia with the DM2 mutation. Both types of DM belong to the group of most variable human disorders distressing almost all systems of the human body

Objectives

Findings

Conclusion