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The High Level of Aberrant Splicing of ISCU in Slow-Twitch Muscle May Involve the Splicing Factor SRSF3
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.ORCID iD: 0000-0001-6632-5770
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience, Umeå University Hospital, Umeå, Sweden .
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0165453Article in journal (Refereed) Published
Abstract [en]

Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intronic one-base mutation in the iron-sulfur cluster assembly (ISCU) gene, resulting in aberrant splicing. The incorrectly spliced transcripts contain a 100 or 86 bp intron sequence encoding a non-functional ISCU protein, which leads to defects in several Fe-S containing proteins in the respiratory chain and the TCA cycle. The symptoms in HML are restricted to skeletal muscle, and it has been proposed that this effect is due to higher levels of incorrectly spliced ISCU in skeletal muscle compared with other energy-demanding tissues. In this study, we confirm that skeletal muscle contains the highest levels of incorrect ISCU splice variants compared with heart, brain, liver and kidney using a transgenic mouse model expressing human HML mutated ISCU. We also show that incorrect splicing occurs to a significantly higher extent in the slow-twitch soleus muscle compared with the gastrocnemius and quadriceps. The splicing factor serine/arginine-rich splicing factor 3 (SRSF3) was identified as a potential candidate for the slow fiber specific regulation of ISCU splicing since this factor was expressed at higher levels in the soleus compared to the gastrocnemius and quadriceps. We identified an interaction between SRSF3 and the ISCU transcript, and by overexpressing SRSF3 in human myoblasts we observed increased levels of incorrectly spliced ISCU, while knockdown of SRSF3 resulted in decreased levels. We therefore suggest that SRSF3 may participate in the regulation of the incorrect splicing of mutant ISCU and may, at least partially, explain the muscle-specific symptoms of HML.

Place, publisher, year, edition, pages
Public library science , 2016. Vol. 11, no 10, e0165453
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-129745DOI: 10.1371/journal.pone.0165453ISI: 000389602800075PubMedID: 27783661OAI: oai:DiVA.org:umu-129745DiVA: diva2:1063280
Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2017-05-11Bibliographically approved

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Rawcliffe, Denise F. R.Österman, LennartLindsten, HansHolmberg, Monica
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