Insulin Receptor Splicing Alteration in Myotonic Dystrophy Type 2

Abstract

Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions.

MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T

“…For example, for the fifth exon of the cardiac troponin T (cTNT) pre-mRNA, CUG-BP is a positive regulator of exon five inclusion while MBNL is a negative regulator of exon five inclusion (Philips et al 1998;Ho et al 2004Ho et al , 2005a. Conversely, for exon 11 of the insulin receptor pre-mRNA, the roles of CUG-BP and MBNL have been reversed and CUG-BP is a negative regulator while MBNL is a positive regulator (Savkur et al 2001(Savkur et al , 2004Dansithong et al 2005;Paul et al 2006).…”

Anesthésie et dystrophie myotonique de type 2: une série de cas

“…14 Diabetes mellitus is common in DM2 and is a result of altered insulin receptors on skeletal muscle that contribute to insulin resistance in this disorder. 16 In our series, diabetes mellitus was present in four adult patients. There were no clinically significant elevated plasma glucose levels among non-diabetic adult patients in this series; however, perioperative glucose levels were not obtained consistently, and hyperglycemia may have been unrecognized in these cases.…”

Progress in therapeutic antisense applications for neuromuscular disorders

“…Decreased levels of MBLN and increased levels of CUGBP led to a synergistic misregulation of alternative splicing of a number of genes, including a muscle-specific chloride channel (ClC-1), 88 cardiac troponin 2 (TNNT2) 86 and the insulin receptor (INSR). 89 For each gene, the fetal isoform rather than the adult isoform is expressed in MD patients. There is strong evidence that the misregulation of certain transcripts leads to different aspects of the disease, for example, ClC-1 misregulation leads to myotonia, INSR to insulin resistance and TNNT2 to cardiac conduction defects.…”