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Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy

Lookup NU author(s): Dr Vanessa Hogan, Dr Langping He, Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert Taylor


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Hereditary myopathy with lactic acidosis, or myopathy with exercise intolerance. Swedish type (OMIM #255125) is caused by mutations in the iron-sulfur cluster scaffold (ISCU) gene. The g.7044G>C ISCU mutation induces a splicing error in the pre-mRNA that strengthens a weak intronic splice site leading to inclusion of a new exon and subsequent loss of mRNA and protein. While ISCU is widely expressed, homozygosity for this particular intronic mutation gives rise to a pure myopathy. In order to investigate tissue specificity and disease mechanism, we studied muscle, myoblasts, fibroblasts and blood cells from the first non-Swedish case of this disease. Consistent with the recognised role of ISCU, we found abnormal activities of respiratory chain complexes containing iron-sulfur clusters in patient muscle. We confirmed that, in the presence of the g.7044G>C mutation, splicing produces both abnormally and normally spliced mRNA in all tissues. The ratio of these products varies dramatically between tissues, being most abnormal in mature skeletal muscle that also has the lowest relative starting levels of ISCU mRNA compared with other tissues. Myoblasts and fibroblasts have more of the normally spliced variant as well as higher starting levels of ISCU mRNA. Up-regulation of mtDNA copy number was found in skeletal muscle and myoblasts, but not fibroblasts, and is thought to represent a compensatory response. Tissue specificity in this disorder appears therefore to be dependent on the mRNA starting level, the amount of remaining normally spliced RNA, and the degree to which compensatory mechanisms can respond. (C) 2010 Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Sanaker PS, Toompuu M, Hogan VE, He LP, Tzoulis C, Chrzanowska-Lightowlers ZMA, Taylor RW, Bindoff LA

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta: Molecular Basis of Disease

Year: 2010

Volume: 1802

Issue: 6

Pages: 539-544

Print publication date: 04/03/2010

ISSN (print): 0925-4439

ISSN (electronic): 0006-3002

Publisher: Elsevier BV


DOI: 10.1016/j.bbadis.2010.02.010


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Funder referenceFunder name
Heise Vest RHF
Norwegian Research Council
074454/Z/04/ZWellcome Trust