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

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• 作者：Z. Luk&aacute ; &scaron ; ^a ; ¹ ; ^{zlukas@nbox.cz} ; ^{zlukas@fnbrno.cz} ; M. Falk^b ; ¹ ; ^{mfalk@seznam.cz} ; J. Feit^a ; O. Sou膷ek^a ; I. Falkov&aacute ; ^a ; ^b ; L. &Scaron ; tefan膷&iacute ; kov&aacute ; ^b ; E. Janou&scaron ; ov&aacute ; ^c ; L. Fajkusov&aacute ; ^d ; J. Zaor&aacute ; lkov&aacute ; ^a ; R. Hrab&aacute ; lkov&aacute ; ^a
• 关键词：Myotonic dystrophy ; Transcription of ZNF9 ; CCUG repeat expansion ; Sequestration of MBNL1 protein ; Ribonuclear foci ; Insulin receptor alternative splicing
• 刊名：Neuromuscular Disorders
• 出版年：2012
• 期刊代码：203_09608966
• 类别：med
• 出版时间：July, 2012
• 卷：22
• 期：7
• 页码：604-616
• 文件大小：1436 K

摘要

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 CCUG^exp RNA transcripts of the <em>ZNF9em> 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 CCUG^exp foci, a different expression pattern of MBNL1 protein and a different sequestration of MBNL1 by CCUG^exp repeats in skeletal muscle, vascular smooth muscle and endothelia, Schwann cells, adipocytes, and ectodermal derivatives. The level of CCUG^exp 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.