Altered expression and splicing of Ca2+metabolism genes in myotonic dystrophies DM1 and DM2

Autor:	Bjarne Udd, Mark Screen, Olayinka Raheem, Linda L. Bachinski, Tiina Suominen, Ralf Krahe, Anna Vihola, Mario Sirito
Rok vydání:	2013
Předmět:	musculoskeletal diseases 0303 health sciences Histology Microarray analysis techniques Alternative splicing Biology medicine.disease Myotonic dystrophy Molecular biology Sarcoplasmic reticulum lumen 3. Good health Pathology and Forensic Medicine Gene expression profiling 03 medical and health sciences 0302 clinical medicine Neurology Physiology (medical) Calcium-binding protein Gene expression RNA splicing medicine Neurology (clinical) 030217 neurology & neurosurgery 030304 developmental biology
Zdroj:	Neuropathology and Applied Neurobiology. 39:390-405
ISSN:	0305-1846
DOI:	10.1111/j.1365-2990.2012.01289.x
Popis:	A. Vihola, M. Sirito, L. L. Bachinski, O. Raheem, M. Screen, T. Suominen, R. Krahe and B. Udd (2013) Neuropathology and Applied Neurobiology39, 390–405 Altered expression and splicing of Ca2+ metabolism genes in myotonic dystrophies DM1 and DM2 Aims: Myotonic dystrophy types 1 and 2 (DM1 and DM2) are multisystem disorders caused by similar repeat expansion mutations, with similar yet distinct clinical features. Aberrant splicing of multiple effector genes, as well as dysregulation of transcription and translation, has been suggested to underlie different aspects of the complex phenotypes in DM1 and DM2. Ca2+ plays a central role in both muscle contraction and control of gene expression, and recent expression profiling studies have indicated major perturbations of the Ca2+ signalling pathways in DM. Here we have further investigated the expression of genes and proteins involved in Ca2+ metabolism in DM patients, including Ca2+ channels and Ca2+ binding proteins. Methods: We used patient muscle biopsies to analyse mRNA expression and splicing of genes by microarray expression profiling and RT-PCR. We studied protein expression by immunohistochemistry and immunoblotting. Results: Most of the genes studied showed mRNA up-regulation in expression profiling. When analysed by immunohistochemistry the Ca2+ release channel ryanodine receptor was reduced in DM1 and DM2, as was calsequestrin 2, a sarcoplasmic reticulum lumen Ca2+ storage protein. Abnormal splicing of ATP2A1 was more pronounced in DM2 than DM1. Conclusions: We observed abnormal mRNA and protein expression in DM affecting several proteins involved in Ca2+ metabolism, with some differences between DM1 and DM2. Our protein expression studies are suggestive of a post-transcriptional defect(s) in the myotonic dystrophies.
Databáze:	OpenAIRE
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