Sequestration of MBNL1 in tissues of patients with myotonic dystrophy type 2

• Published in: Neuromuscular disorders : NMD Vol. 22; no. 7; pp. 604 - 616
• Main Authors: Lukáš, Z, Falk, M, Feit, J, Souček, O, Falková, I, Štefančíková, L, Janoušová, E, Fajkusová, L, Zaorálková, J, Hrabálková, R
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01-07-2012
• Subjects: Actins - metabolism; Adipocytes - metabolism; Adipocytes - pathology; Analysis of Variance; Antigens, CD34 - metabolism; CCUG repeat expansion; Endothelium - metabolism; Endothelium - pathology; Humans; Insulin receptor alternative splicing; Microscopy, Confocal; Muscle, Skeletal - metabolism; Myotonic Disorders - diagnosis; Myotonic Disorders - genetics; Myotonic Disorders - metabolism; Myotonic Disorders - pathology; Myotonic Dystrophy; Neurofilament Proteins - metabolism; Neurology; Protein Transport - physiology; Receptor, Insulin - genetics; Repetitive Sequences, Nucleic Acid - genetics; Ribonuclear foci; RNA - metabolism; RNA Splicing - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; S100 Proteins - metabolism; Sequestration of MBNL1 protein; Skin - metabolism; Skin - pathology; Transcription of ZNF9; Ribonuclear foci; Transcription of ZNF9; Insulin receptor alternative splicing; Sequestration of MBNL1 protein; Myotonic dystrophy; CCUG repeat expansion
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2012.03.004

Abstract The pathogenesis of myotonic dystrophy type 2 includes the sequestration of MBNL proteins by expanded CCUG transcripts, which leads to an abnormal splicing of their target pre-mRNAs. We have found CCUGexp RNA transcripts of the ZNF9 gene associated with the formation of ribonuclear foci in human skeletal muscle and some non-muscle tissues present in muscle biopsies and skin excisions from myotonic dystrophy type 2 patients. Using RNA-FISH and immunofluorescence-FISH methods in combination with a high-resolution confocal microscopy, we demonstrate a different frequency of nuclei containing the CCUGexp foci, a different expression pattern of MBNL1 protein and a different sequestration of MBNL1 by CCUGexp repeats in skeletal muscle, vascular smooth muscle and endothelia, Schwann cells, adipocytes, and ectodermal derivatives. The level of CCUGexp transcription in epidermal and hair sheath cells is lower compared with that in other tissues examined. We suppose that non-muscle tissues of myotonic dystrophy type 2 patients might be affected by a similar molecular mechanism as the skeletal muscle, as suggested by our observation of an aberrant insulin receptor splicing in myotonic dystrophy type 2 adipocytes.