| 1. |
- Mochel, Fanny, et al.
(författare)
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Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance
- 2008
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 82:3, s. 652-660
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Tidskriftsartikel (refereegranskat)abstract
- A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.
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| 2. |
- Ranganathan, Srikanth, et al.
(författare)
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Therapeutic approaches to spinal and bulbar muscular atrophy.
- 2010
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Ingår i: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147. ; Okt, s. 523-527
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Tidskriftsartikel (refereegranskat)abstract
- Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism probably involves a toxic gain of function in the mutant protein, because other mutations that cause a loss of androgen receptor function result in a different phenotype and the mutant protein is toxic in mouse models. In these models, the toxicity is ligand-dependent and is associated with protein aggregation, as well as altered transcriptional regulation, axonal transport and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction, heat shock protein 90 (HSP90) inhibition and insulin-like growth factor (IGF)-1 overexpression. Clinical trials of androgen-reducing agents have had mixed results, with indications of efficacy but no proof of clinically meaningful benefit to date. These clinical studies have established outcome measures for future trials of other agents that have been beneficial in animal studies.
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