Human Molecular Genetics Advance Access published online on February 23, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn057
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Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect
1 Medical and Clinical Genetics Unit, Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden 2 Anatomy Unit, Department of Integrative Medical Biology, Umeå University, SE-901 87 Umeå, Sweden
* Medical and Clinical Genetics Unit, Department of Medical Biosciences, Umeå University, SE-901 87 Umeå, Sweden, Fax: +46-90-130760, phone: +46-90-785 4406, e-mail: monica.holmberg{at}medbio.umu.se
Received January 25, 2008; Revised February 20, 2008; Accepted February 20, 2008
We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea, and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene—ISCU—specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1,000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element, ISRE, but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint first authors.
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